Article

Incidence and Clinical Features of Ganciclovir- Resistant Cytomegalovirus Disease in Heart Transplant Recipients

September 2007
Clinical Infectious Diseases 45(4):439-47

September 2007
45(4):439-47

DOI:10.1086/519941

Source
PubMed

Authors:

The incidence and clinical and virologic aspects of ganciclovir-resistant cytomegalovirus (CMV) disease have not been well-characterized in heart transplant recipients. We retrospectively analyzed all patients who underwent their first heart transplantation during the period from 1 January 1995 through 30 June 2005 at a single health care center. Cox proportional hazard regression was used to assess the relationship between clinical variables and CMV disease. Portions of the UL97 gene were sequenced in patients with slow clinical and/or virologic response to ganciclovir therapy. Cytomegalovirus disease developed in 32 (11.7%) of 274 patients at a median of 4.2 months after transplantation (range, 1.8-11.6 months after transplantation) and was independently associated with donor-seropositive/recipient-seronegative (D+/R-) serostatus (adjusted hazard ratio, 6.93; P<.001). The incidence of ganciclovir-resistant CMV disease was 1.5% overall (4 of 274 patients), 5% among D+/R- serostatus recipients (4 of 80 patients), and 12.5% among patients who developed CMV disease (4 of 32 patients). Ganciclovir-resistant CMV disease was significantly associated with D+/R- serostatus (4 [5%] of 80 vs. 0 [0%] of 153 patients; P=.02), greater prior exposure to ganciclovir (median duration of exposure, 150 vs. 69 days; P=.003), and substantial morbidity, including prolonged CMV-associated hospitalization (median duration of hospitalization, 66 vs. 0 days; P<.01). CMV disease, including ganciclovir-resistant disease, is an important clinical problem in D+/R- heart transplant recipients who receive antiviral prophylaxis. Strategies specifically designed to reduce the incidence and impact of CMV disease in this population are warranted.

Reporte de caso de resistencia al ganciclovir en enfermedad por citomegalovirus postrasplante cardiaco

Article

Full-text available

Mar 2018
Rev Peru Med Exp Salud Publica

Cytomegalovirus infection after a heart transplant is a recurrent medical condition. Its frequency increases when the donors are serum-positive, and the recipients are serum-negative to this virus. In the pediatric population, the infection only develops in a small percentage and the patients rarely present resistance to conventional treatment with ganciclovir and valganciclovir. We presented the first report of a pediatric case of the cytomegalovirus infection resistant to ganciclovir and valganciclovir after a heart transplant in a Peruvian public hospital with an unusual presentation. The resistance to these drugs was evident after 277 days of evolution of the disease considering the non-remission of the symptomatology and the persistence of an elevated viral load. The administration of foscarnet led to a clinical and laboratory improvement until remission of the disease.

Risk Factors and Outcomes of Ganciclovir Resistant Cytomegalovirus Infection in Solid Organ Transplant Recipients

Article

Mar 2017
CLIN INFECT DIS

Background: Ganciclovir-resistant (ganR)-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 be appropriately 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 Chi-square (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, 4.1% (32/777) among D+R- patients, and was stable over the study period. GanR-CMV was associated with increased prior exposure to ganciclovir (median 153 vs. 91 days, p<0.001). Eighteen percent (3/17) of lung transplant recipients with ganR-CMV had received <6 weeks of prior ganciclovir (current guideline-recommended resistance testing threshold) and all non-lung recipients had received ?90 days (median 160, range 90-284 days) prior to diagnosis of ganR CMV. GanR-CMV was associated with higher mortality (11% vs. 1%, p=0.004), fewer days alive and non-hospitalized (73 vs. 81, p=0.039) and decreased renal function (42% vs 19%, p=0.008) by three months after diagnosis. Conclusions: GanR-CMV is associated with longer prior antiviral duration and higher attributable morbidity and mortality than ganS-CMV. Upcoming revised CMV guidelines should incorporate organ transplant specific thresholds of prior drug exposure to guide rational ganR-CMV testing in SOT recipients. Improved strategies for prevention and treatment of ganR-CMV are warranted.

Cytomegalovirus disease in post-heart-transplant patients at a national reference center

Article

Full-text available

Dec 2016
REV CHIL INFECTOL

Introduction: Heart transplantation remains as the treatment of choice when the heart failure is refractory to the medical or surgical therapy. Therefore, cytomegalovirus disease is an important post-heart-transplant infectious complication. Aims: To describe the prevalence and clinical characteristics of the cytomegalovirus disease after heart transplant surgery. Materials and Methods: A retrospective, descriptive study was conducted. It enrolled 35 heart-transplant patients attended in the Cardiovascular National Institute (INCOR), between 2010 and 2015. The information was obtained through the review of medical records. The demographic and relevant clinical variables were analyzed for the cytomegalovirus disease cases. Results: The population mean age was 39.49 +/- 15.07 years and most of them were male patients (63%). The prevalence of the cytomegalovirus disease was 5.7% (two patients), both were seronegative for cytomegalovirus before transplantation. One of the patients had the disease before finishing the valganciclovir prophylaxis and the other after the end of it. Conclusion: The prevalence of the cytomegalovirus disease is slightly lower than in other studies. Moreover, the cytomegalovirus disease can remit with a prompt diagnosis and the proper medical treatment.

CMV Immunoglobulins for the Treatment of CMV Infections in Thoracic Transplant Recipients

Article

Full-text available

Mar 2016

Intravenous ganciclovir and, increasingly, oral valganciclovir are now considered the mainstay of treatment for cytomegalovirus (CMV) infection or CMV disease. Under certain circumstances, CMV immunoglobulin (CMVIG) may be an appropriate addition or, indeed, alternative. Data on monotherapy with CMVIG are limited, but encouraging, for example in cases of ganciclovir intolerance. In cases of recurrent CMV in thoracic transplant patients after a disease- and drug-free period, adjunctive CMVIG can be considered in patients with hypogammaglobulinemia. Antiviral-resistant CMV, which is more common among thoracic organ recipients than in other types of transplant, can be an indication for introduction of CMVIG, particularly in view of the toxicity associated with other options, such as foscarnet. Due to a lack of controlled trials, decision-making is based on clinical experience. In the absence of a robust evidence base, it seems reasonable to consider the use of CMVIG to treat CMV in adult or pediatric thoracic transplant patients with ganciclovir-resistant infection, or in serious or complicated cases. The latter can potentially include (i) treatment of severe clinical manifestations, such as pneumonitis or eye complications; (ii) patients with a positive biopsy in end organs, such as the lung or stomach; (iii) symptomatic cases with rising polymerase chain reaction values (for example, higher than 5.0 log10) despite antiviral treatment; (iv) CMV disease or CMV infection or risk factors, such as CMV-IgG-negative serostatus; (vi) ganciclovir intolerance; (vii) patients with hypogammaglobulinemia.

Cytomegalovirus Infections in Pediatric Solid Organ Transplant Patients

Article

Dec 2012

Cytomegalovirus (CMV) is one of the most important infectious agents after organ transplantation in children as it gives rise to morbidity, loss of the graft and mortality. CMV infection/disease is full of unknowns in terms of both prevention and treatment strategies in children; mostly, studies and guidelines for adult patients are used while the child is being evaluated. The serostatus of the donor and the recipient, the type of the organ transplanted and immunosuppressive treatment are risk factors of the disease, similar to adult patients. Pre-emptive combination prophylaxis and hybrid strategies are also used in children. These have both advantages and disadvantages but they can be used in children efficiently. Gancyclovir is used as the first drug choice for CMV and some recent studies suggest that valgancyclovir is also efficient in children. The choice of drug, the dosage of the drug, the duration of prophylaxis/treatment, the side effects of drug, the time required for tests during infection/disease and the efficacy of adjunctive treatment in children are questions that are waiting to be researched, and must be answered with multicenter, randomized and controlled studies.

GENETIC FACTORS OF CYTOMEGALOVIRUS AND OTHER HERPESVIRUSES THAT INFLUENCE OUTCOMES OF ANTIVIRAL THERAPY IN TRANSPLANTATION

Article

Jenna M Iwasenko

Analysis of Ganciclovir-Resistant Cytomegalovirus Infection Caused by the UL97 Gene Mutation in Codons 460 and 520 in Pediatric Patients: A Case Series

Article

Full-text available

Nov 2019

Background Drug-resistant cytomegalovirus (CMV) infection has been increasingly recognized. However, there are limited data in pediatric patients. In this study, the prevalence and factors associated with CMV infection with UL97 mutations in pediatric patients treated with ganciclovir but not responding to treatment were evaluated. Methods This retrospective study was conducted from January 2013 to December 2017. All patients who were suspected of having ganciclovir-resistant CMV infection and had never had ganciclovir prophylaxis were included. Genotypic assay for UL97 mutations in codons 460 and 520 conferring ganciclovir resistance was performed. Factors associated with the presence of UL97 mutations were analyzed. Results Of 34 patients included, 10 patients (29.4%) had a genotypically confirmed UL97 mutation. The median age (interquartile range [IQR]) was 3 (0.85–8.68) years. Ganciclovir resistance was tested at a median time (IQR) of 22.5 (14.3–31) days after initiation of ganciclovir. All resistant isolates harbored a UL97 mutation in codon 460. Compared with patients infected with CMV without UL97 mutation, those infected with UL97 mutation strains were younger (median age [IQR], 3.02 [0.85–8.68] vs 10.45 [2.7–16.4] years) and had a higher maximum viral load (median [IQR], 5.06 [4.74–6.05] vs 4.42 [4.03–4.87] copies/mL). Six of 10 (60%) patients were successfully treated with high-dose ganciclovir (7.5 mg/kg twice daily). Conclusions UL97 mutation ganciclovir-resistant CMV infection was not uncommon in the pediatric population. Screening for this mutation should be considered in patients experiencing virological worsening while ganciclovir is given, even if patients have not previously received ganciclovir prophylaxis.

The D-form of a novel heparan binding peptide decreases cytomegalovirus infection in vivo and in vitro

Article

Sep 2016

Human cytomegalovirus (HCMV) infection in utero can lead to congenital sensory neural hearing loss and mental retardation. Reactivation or primary infection can increase the morbidity and mortality in immune suppressed transplant recipients and AIDS patients. The current standard of care for HCMV disease is nucleoside analogs, which can be nephrotoxic. In addition resistance to current treatments is becoming increasingly common. In an effort to develop novel CMV treatments, we tested the effectiveness of the D-form of a novel heparan sulfate binding peptide, p5RD, at reducing infection of ganciclovir (GCV) resistant HCMVs in vitro and MCMV in vivo. HCMV infection was reduced by greater than 90% when cells were pretreated with p5RD. Because p5RD acts by a mechanism unrelated to those used by current antivirals, it was effective at reducing GCV resistant HCMVs by 85%. We show that p5RD is resistant to common proteases and serum inactivation, which likely contributed to its ability to significantly reduced infection of peritoneal exudate cells and viral loads in the spleen and the lungs in vivo. The ability of p5RD to reduce HCMV infectivity in vitro including GCV resistant HCMVs and MCMV infection in vivo suggests that this peptide could be a novel anti-CMV therapeutic.

Factors Associated With Genotypic Resistance and Outcome Among Solid Organ Transplant Recipients With Refractory Cytomegalovirus Infection

Article

Full-text available

Jun 2023
TRANSPL INT

Genotypically resistant cytomegalovirus (CMV) infection is associated with increased morbi-mortality. We herein aimed at understanding the factors that predict CMV genotypic resistance in refractory infections and disease in the SOTR (Solid Organ Transplant Recipients) population, and the factors associated with outcomes. We included all SOTRs who were tested for CMV genotypic resistance for CMV refractory infection/disease over ten years in two centers. Eighty-one refractory patients were included, 26 with genotypically resistant infections (32%). Twenty-four of these genotypic profiles conferred resistance to ganciclovir (GCV) and 2 to GCV and cidofovir. Twenty-three patients presented a high level of GCV resistance. We found no resistance mutation to letermovir. Age (OR = 0.94 per year, IC95 [0.089–0.99]), a history of valganciclovir (VGCV) underdosing or of low plasma concentration (OR= 5.6, IC95 [1.69–20.7]), being on VGCV at infection onset (OR = 3.11, IC95 [1.18–5.32]) and the recipients’ CMV negative serostatus (OR = 3.40, IC95 [0.97–12.8]) were independently associated with CMV genotypic resistance. One year mortality was higher in the resistant CMV group (19.2 % versu s 3.6 %, p = 0.02). Antiviral drugs severe adverse effects were also independently associated with CMV genotypic resistance. CMV genotypic resistance to antivirals was independently associated with a younger age, exposure to low levels of GCV, the recipients’ negative serostatus, and presenting the infection on VGCV prophylaxis. This data is of importance, given that we also found a poorer outcome in the patients of the resistant group.

Impact of anti-CMV IgG titers and CD34 count prior to hematopoietic stem cell transplantation from alternative donors

Article

Full-text available

Aug 2020
BIOL BLOOD MARROW TR

Cytomegalovirus(CMV) reactivation remains one of the main infectious complications following hematopoietic stem cell transplantation(HSCT). The objectives of this paper are to study the role of anti-CMV antibodies titers in HSCT from alternative donors and to compare the CMV reactivation risks between posttransplant cyclophosphamide-based haploidentical HSCT and ATG-based URD HSCT. We included 98 CMV-positive patients, 30 undergoing haploidentical and 68, URD transplantation. Most patients had malignant diseases(84%), received myeloablative(78%) conditioning regimen and bone marrow graft(90%). The median pre-transplant anti-CMV IgG level was 109 U/mL. With median follow-up of 2.2 years, there were 72 CMV reactivations in 50 patients. There was no difference in CMV reactivation patterns between haploidentical and URD transplants. In multivariable analysis until the first event, the incidence of CMV reactivation was higher in patients with anti-CMV IgG levels greater than 100 U/mL(HR=2.38, p=0.005), in patients diagnosed with grades II-IV acute graft versus host disease(HR=10.8, p=0.003, after D+50) and lower in those who received higher doses of CD34 cells(HR=0.44, p=0.006). In multivariable analysis for recurring events, the incidence of CMV reactivation was higher in patients receiving reduced-intensity conditioning(HR=1.69, p=0.04) and in patients with acuted GVHD(HR=1.88, p=0.02), and lower in those who received higher doses of CD34 cells(HR=0.55, p=0.01). In summary, we have shown that pre-transplant anti-CMV IgG titers are correlated with CMV reactivation risk. More studies are needed to assess how this information can be incorporated in. High cellular grafts, which is a modifiable risk factor, also protects against CMV reactivation.

Impact of Valganciclovir Prophylaxis Duration on Cytomegalovirus Disease in High‐Risk Donor Seropositive/Recipient Seronegative Heart Transplant Recipients

Article

Full-text available

Feb 2020

Background: Few data support use of 6 over 3 months of antiviral prophylaxis for cytomegalovirus (CMV) disease prevention in donor seropositive/recipient seronegative (D+R-) heart transplant recipients (HTR). Methods: We retrospectively assessed CMV disease and outcomes in 310 adult HTR between 7/5/2005 - 12/30/2016 at our center. Valganciclovir (VGCV) prophylaxis was given for 3-6 months in the D+R- group. Multivariable models evaluated risk factors for CMV disease in patients who received 3 vs 6 months (±1 month) of prophylaxis, with investigation of inverse probability weighting to correct for confounding variables. Results: The incidence of CMV disease among all patients and the D+R- group was 8.7% (27/310) and 26.5% (22/83), respectively, and included syndrome in 22.2% (6/27) and end-organ involvement in 77.8% (21/27). In a multivariable model, 6 vs 3 months of antiviral prophylaxis was not associated with reduced risk for CMV disease (OR 2.28 [95% CI 0.66, 7.91], p=0.19). CMV disease in D+R- HTR was associated with higher rates of hospitalization (87.5% [14/16] vs 6.3% [1/16], p<0.001) and for a longer duration than in matched D+R- controls without disease. Conclusions: CMV disease remains a major cause of morbidity in D+R- HTR. In contrast to documented benefit in D+R- lung and kidney recipients, VGCV duration of 6 months was not associated with a lower incidence of CMV disease in D+R- HTR compared to 3 month duration, and should be reconsidered in this patient population.

Anticytomegalovirus Peptides Point to New Insights for CMV Entry Mechanisms and the Limitations of In Vitro Screenings

Article

Full-text available

Feb 2019

In the absence of an effective vaccine to prevent HCMV infections, alternative interventions must be developed. Prevention of viral entry into susceptible cells is an attractive alternative strategy. Here we report that heparan sulfate-binding peptides effectively inhibit entry into fibroblasts of in vitro- derived CMVs and partially inhibit in vivo- derived CMVs. This includes the inhibition of urine-derived HCMV (uCMV), which is highly resistant to antibody neutralization. While these antiviral peptides are highly effective at inhibiting cell-free virus, they do not inhibit MCMV cell-to-cell spread. This underscores the need to understand the mechanism of cell-to-cell spread and differences between in vivo -derived versus in vitro- derived CMV entry to effectively prevent CMV’s spread.

There Is Always Another Way! Cytomegalovirus’ Multifaceted Dissemination Schemes

Article

Full-text available

Jul 2018

Human cytomegalovirus (HCMV) is a β-herpes virus that is a significant pathogen within immune compromised populations. HCMV morbidity is induced through viral dissemination and inflammation. Typically, viral dissemination is thought to follow Fenner’s hypothesis where virus replicates at the site of infection, followed by replication in the draining lymph nodes, and eventually replicating within blood filtering organs. Although CMVs somewhat follow Fenner’s hypothesis, they deviate from it by spreading primarily through innate immune cells as opposed to cell-free virus. Also, in vivo CMVs infect new cells via cell-to-cell spread and disseminate directly to secondary organs through novel mechanisms. We review the historic and recent literature pointing to CMV’s direct dissemination to secondary organs and the genes that it has evolved for increasing its ability to disseminate. We also highlight aspects of CMV infection for studying viral dissemination when using in vivo animal models.

CMV Infection in Kidney Transplanted Patients

Article

Jul 2012

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.

Epidemiology and Outcome of Ganciclovir-Resistant Cytomegalovirus Infection After Solid Organ Transplantation: A Single Transplant Center Experience in Thailand

Article

Jun 2017
TRANSPL P

Background Data on drug-resistant cytomegalovirus (CMV) infection in solid organ transplantation (SOT) are not often reported from resource-limited settings. We aimed to investigate the epidemiology and outcomes of this infection in SOT recipients at our institution. Methods This was a retrospective study conducted from January 2012 to May 2015. We included all SOT recipients who were suspected for drug-resistant CMV infection. Genotypic assay for UL97 gene mutation was analyzed by real-time polymerase chain reaction. Patients were reviewed for demographic data, clinical presentation, virologic data, treatment, and outcomes. Results The population consisted of 18 (12 kidney, 6 liver) SOT recipients with a median age of 20 years (interquartile range [IQR], 1–49); 44% were male. Anti-CMV resistance testing was analyzed at a median time of 23 days (IQR, 14–33) after initiation of anti-CMV therapy with a median CMV load of log 3.79 copies/mL (IQR, 3.37–4.58). During a median period of 2 years (IQR, 1–3), 6 SOT recipients were identified with UL97 gene mutation in codon 460, conferring ganciclovir (GCV) resistance. Patients with UL97 gene mutation had a longer mean duration of CMV DNAemia compared with those without mutation (263 vs 107 days; P = .04). All patients received high-dose GCV. Two patients received foscarnet and cidofovir. Two patients died (non–CMV-related), and 4 patients. Conclusions GCV-resistant CMV infection in SOT recipients is an emerging clinical problem in resource-limited country. Those with UL97 mutation CMV infection have prolonged duration of CMV DNAemia. Clinicians should be aware of this condition when caring for SOT recipients.

Use of Cidofovir for Cytomegalovirus Disease Refractory to Ganciclovir in Solid Organ Recipients

Article

Nov 2016
Surg Infect

Background: Solid organ transplantation (SOT) frequently is complicated by cytomegalovirus (CMV) infections. Cidofovir (CDV) is active against CMV, including many ganciclovir (GCV)-resistant mutants, but often is considered to be too nephrotoxic for use after organ transplantation. Patients and methods: Seven males and two females (median age 50.1 years), including two kidney/pancreas, four lung, one small bowel, and two hand recipients, received CDV for refractory CMV disease. Results: Three recipients were CMV seronegative, but all nine received grafts from CMV-seropositive donors. Five patients were given antithymocyte globulin, four received daclizumab induction, seven experienced rejection (five with multiple episodes), and one suffered from common variable immunodeficiency. Six presented with other infections (five invasive fungal and four bacterial). Eight patients had received prophylactic GCV, and eight had been treated for CMV infection/disease (GCV eight; CMV immunoglobulin three; foscarnet three). The indications for CDV were UL97 CMV mutation (n = 2), GCV-induced neutropenia with continued CMV disease (n = 4), and clinical resistance to GCV (n = 3). Seven patients cleared CMV, and two had a partial response. Four experienced CMV relapse requiring GCV (n = 2), repeat CDV (n = 1), or CMV immunoglobulin (n = 1). Four patients had mild nephrotoxicity, and three developed renal failure, all in association with additional factors. No patient died directly from CMV disease alone. Two patients died of uncontrolled infections and concurrent CMV disease, one with invasive aspergillosis and another with nocardiosis. Conclusions: Cidofovir was useful for the treatment of GCV-refractory CMV disease after SOT. Although nephrotoxicity was a common complication of CDV, several patients completed a course of therapy successfully and demonstrated effective treatment of CMV disease.

The First Case of Ganciclovir-Resistant Cytomegalovirus Colitis with a 597-600 Deletion in UL97 Gene after Stem Cell Transplantation in Korea

Article

Full-text available

Jan 2015

Human cytomegalovirus (CMV) infection has been a major concern in hematopoietic stem cell transplant recipients. Ganciclovir (GCV) resistance results mostly from mutations within the protein kinase UL97 gene. The three hot spots for GCV resistance (codons 460, 520, and 590-607) were well known. We describe a case of GCV-resistant CMV colitis caused by a 597-600 deletion in UL97 after haplo-identical peripheral blood stem cell transplantation (h-PBSCT) in a 46 year-old man with myelodysplastic syndrome. On post-PBSCT day 28, CMV antigenemia turned positive. Treatment of GCV was started and continued for 12 weeks but CMV antigenemia did not respond to the treatment and CMV colitis was worsened. The UL97 showed the in-frame deletion between codons 597 and 600 by direct sequencing. The treatment was switched to foscarnet and the antigenemia test was consecutively negative twice, and clinical symptoms improved. Despite the recovery of the patient from CMV colitis, the patient expired post-PBSCT day 146 from acute liver failure, hepatorenal syndrome and septic shock. This case is a first report of a deletion 597-600 in CMV UL97 in Korea. A 597-600 deletion in UL97 was responsible for the GCV resistance while preserving susceptibility to foscarnet.

Novel Heparan Sulfate-Binding Peptides for Blocking Herpesvirus Entry

Article

Full-text available

May 2015
PLOS ONE

Human cytomegalovirus (HCMV) infection can lead to congenital hearing loss and mental retardation. Upon immune suppression, reactivation of latent HCMV or primary infection increases morbidity in cancer, transplantation, and late stage AIDS patients. Current treatments include nucleoside analogues, which have significant toxicities limiting their usefulness. In this study we screened a panel of synthetic heparin-binding peptides for their ability to prevent CMV infection in vitro. A peptide designated, p5+14 exhibited ~ 90% reduction in murine CMV (MCMV) infection. Because negatively charged, cell-surface heparan sulfate proteoglycans (HSPGs), serve as the attachment receptor during the adsorption phase of the CMV infection cycle, we hypothesized that p5+14 effectively competes for CMV adsorption to the cell surface resulting in the reduction in infection. Positively charged Lys residues were required for peptide binding to cell-surface HSPGs and reducing viral infection. We show that this inhibition was not due to a direct neutralizing effect on the virus itself and that the peptide blocked adsorption of the virus. The peptide also inhibited infection of other herpesviruses: HCMV and herpes simplex virus 1 and 2 in vitro, demonstrating it has broad-spectrum antiviral activity. Therefore, this peptide may offer an adjunct therapy for the treatment of herpes viral infections and other viruses that use HSPGs for entry.

Cytomegalovirus in children undergoing haematopoietic stem cell transplantation: a diagnostic and therapeutic approach to antiviral resistance

Article

Full-text available

May 2023

Cytomegalovirus (CMV) is a ubiquitous virus which causes a mild illness in healthy individuals. In immunocompromised individuals, such as children receiving haematopoietic stem cell transplantation, CMV can reactivate, causing serious disease and increasing the risk of death. CMV can be effectively treated with antiviral drugs, but antiviral resistance is an increasingly common complication. Available therapies are associated with adverse effects such as bone marrow suppression and renal impairment, making the choice of appropriate treatment challenging. New agents are emerging and require evaluation in children to establish their role. This review will discuss established and emerging diagnostic tools and treatment options for CMV, including antiviral resistant CMV, in children undergoing haematopoietic stem cell transplant.

Cytomegalovirus and other herpesviruses after hematopoietic cell and solid organ transplantation: From antiviral drugs to virus-specific T cells

Article

Jan 2022
TRANSPL IMMUNOL

Herpesviruses can either cause primary infection or may get reactivated after both hematopoietic cell and solid organ transplantations. In general, viral infections increase post-transplant morbidity and mortality. Prophylactic, preemptive, or therapeutically administered antiviral drugs may be associated with serious side effects and may induce viral resistance. Virus-specific T cells represent a valuable addition to antiviral treatment, with high rates of response and minimal side effects. Even low numbers of virus-specific T cells manufactured by direct selection methods can reconstitute virus-specific immunity after transplantation and control viral replication. Virus-specific T cells belong to the advanced therapy medicinal products, and their production is regulated by appropriate legislation; also, strict safety regulations are required to minimize their side effects.

Infection in solid organ transplantation

Chapter

Jan 2010

Antiherpesvirus Agents

Chapter

Mar 2016

Cytomegalovirus Infection in Transplantation

Chapter

Apr 2014

Raymund R Razonable

Study of cytomegalovirus resistance in allogeneic hematopoietic cell transplant recipients

Article

Apr 2020

Introduction Cytomegalovirus (CMV) is the most important opportunistic pathogen associated with transplant. The objective of this study was the characterization of CMV resistance mutations in allogeneic haematopoietic cell transplant recipients (allo-TPH) and the study of associated factors. Methods A retrospective study of a cohort of allo-TPH recipients with post-transplant CMV reactivations with stable or increasing viral loads (CV), despite adequate antiviral treatment for at least 2 weeks. The study of resistance mutations of the UL97 and UL54 genes was carried out by Sanger sequencing. Results Refractory CMV infection in our group of allo-TPH patients corresponded with a 21.43% rate of resistant virus infection (3 of 14 patients). All patients with resistance mutations had multiple reactivation episodes (p-value 0.01). The mutations found were A594V and H520Q in the UL97 gene that confers high-grade resistance to ganciclovir (GCV). One of the 3 cases with antiviral resistance was documented with a low VL (< 1000 copies/ml) and short accumulated GCV treatment (41 days). Conclusion Most of the failures in the treatment of CMV were possibly due to clinical resistance; the lack of satisfactory response to antiviral treatment is not always accompanied by virological resistance. However, the appearance of resistances can occur early after the start of the treatment and with VL below 1000 copies/ml. The number of episodes of reactivation was higher among patients with virological resistance than those who did not.

Global estimate of phenotypic and genotypic ganciclovir resistance in cytomegalovirus infections among HIV and organ transplant patients; A systematic review and meta-analysis

Article

Jan 2020

Human cytomegalovirus (CMV), an opportunistic pathogen belonging to Herpesviridae family, is considered as one of the major causes of morbidity and mortality among wide variety of patients, particularly in transplant recipients and HIV positive patients. As this virus can be resistant to treatment, frequency of CMV in patients who receive organ transplantation and people suffering from AIDS was studied between 1980 and 2019. Medline (via PubMed), Embase, Web of Science, and the Iranian Database were reviewed, and Comprehensive Meta-Analysis (V2.0, Biostat) software analyzed all data. Finally, we used Cochran's Q-statistic to encounter heterogeneity between different studies. Meta-analyses indicated, GCV resistance was 14.1% (95% CI 11.2–17.7); however, in patients suffering from AIDS and organ transplantation were 19.5% (95% CI 14.7–25.4) and 11.4% (95% CI 8.1–15.8), respectively. There were increasing rates in the prevalence of GCV resistance in CMV among transplant recipients, and HIV positive patients. Therefore, evaluation of these refractory infections is beneficial

Cytomegalovirus viremia and resistance patterns in immunocompromised children: An 11-year experience

Article

Dec 2019
PEDIATR HEMAT ONCOL

We noted a recent increase in number of immunocompromised children with CMV viremia at our institution. The purpose of this study was to determine the frequency of CMV viremia in this population and evaluate factors associated with drug-resistant mutations. A retrospective review of immunocompromised hosts, 0-21 years of age, who had CMV viremia during 2007-2017. CMV viremia was detected using PCR assays. Genetic mutation assays were performed using PCR sequencing of the phosophotransferase UL 97 gene and the polymerase UL54 gene of CMV using Quest Diagnostics (San Juan Capistrano, CA, USA) or ARUP Labs (Salt Lake City, UT, USA). Thirty-one patients were identified, including 10 (32%) during the last 2 years. Of the 31 patients, 18 had hematopoietic stem cell transplantation (HSCT), 5 had primary immunodeficiency, 4 had malignancies, 3 had heart transplantation and 1 had new Human Immunodeficiency virus (HIV) infection. Antiviral resistance testing was performed on isolates from seven patients: five with persistent viremia (>1 mo), and two prior to starting antiviral therapy. Resistance was identified in three patients' isolates: two with common variable immunodeficiency (CVID) and one with recurrent Hodgkin's lymphoma who had undergone autologous HSCT. The two patients with CVID had chronic diarrhea and malabsorption and had received prolonged oral valganciclovir courses prior to emergence of resistance. The patient with Hodgkin's lymphoma had received a prolonged IV ganciclovir course. All three tested positive for UL97 mutation and two had both UL97 and UL54 gene mutations. Majority of our patients (21/31) with CMV viremia were transplant recipients and ganciclovir resistance developed in 10%. Two had intestinal malabsorption. Treatment with oral valganciclovir should be avoided in patients with poor gut absorption as that may increase the risk of resistance.

Estudio de resistencias de citomegalovirus en pacientes receptores de trasplante alogénico de progenitores hematopoyéticos

Article

Nov 2019

Introduction: Cytomegalovirus (CMV) is the most important opportunistic pathogen associated with transplant. The objective of this study was the characterization of CMV resistance mutations in allogeneic haematopoietic cell transplant recipients (allo-TPH) and the study of associated factors. Methods: A retrospective study of a cohort of allo-TPH recipients with post-transplant CMV reactivations with stable or increasing viral loads (CV), despite adequate antiviral treatment for at least 2weeks. The study of resistance mutations of the UL97 and UL54 genes was carried out by Sanger sequencing. Results: Refractory CMV infection in our group of allo-TPH patients corresponded with a 21.43% rate of resistant virus infection (3 of 14 patients). All patients with resistance mutations had multiple reactivation episodes (P-value .01). The mutations found were A594V and H520Q in the UL97 gene that confers high-grade resistance to ganciclovir (GCV). One of the 3 cases with antiviral resistance was documented with a low VL (< 1000 copies/ml) and short accumulated GCV treatment (41 days). Conclusion: Most of the failures in the treatment of CMV were possibly due to clinical resistance; the lack of satisfactory response to antiviral treatment is not always accompanied by virological resistance. However, the appearance of resistances can occur early after the start of the treatment and with VL below 1000 copies / ml. The number of episodes of reactivation was higher among patients with virological resistance than those who did not.

Genomic Applications in the Clinical Management of Infectious Diseases

Chapter

Jan 2019

Next-generation sequencing (NGS) technologies are increasingly being used for diagnosis and monitoring of infectious diseases. Here, we review the application of NGS in clinical microbiology focusing on genotypic resistance testing, direct detection of unknown disease-associated pathogens in clinical specimens, investigation of microbial population diversity in the human host, and strain typing. We have organized this chapter into three main sections: (1) applications in clinical virology; (2) applications in clinical bacteriology, mycobacteriology, and mycology; and (3) validation, quality control, and maintenance of proficiency. Though many challenges remain, NGS continues to hold enormous promise for clinical infectious diseases testing.

Resistant Cytomegalovirus Infection in Solid-organ Transplantation: Single-center Experience, Literature Review of Risk Factors, and Proposed Preventive Strategies

Article

Oct 2018
TRANSPL P

Background Cytomegalovirus (CMV) infection causes morbidity and mortality in solid-organ transplant recipients. Drug-resistant CMV is an emerging problem with poor survival outcomes and limited therapeutic options. In this study we comprehensively address the issue of drug resistance in CMV when compared with standard therapies, such as ganciclovir (GCV) and foscarnet. Methods We conducted a retrospective review of adult patients diagnosed with CMV after solid-organ transplant at our center between 2013 and 2017, and identified 7 resistant CMV cases. To study risk factors in the published literature, we performed an extensive database search. Results All patients had documented UL97 mutations, and 3 patients harbored both UL97 and UL54 mutations. For cases with increasing viral load or failure to achieve clinical improvement despite optimal therapy, genetic resistance testing was carried out. Patients received GCV and foscarnet combination therapy. As an adjunct, CMV immunoglobulin, cidofovir, and leflunomide were added. Risk factors, including donor⁺/recipient⁻ serostatus, persistent high viral replication, prolonged therapeutic GCV exposure (>2.5 months), and allograft rejection, were assessed. Conclusion Patients at risk, especially those with D⁺/R⁻ serostatus, should be judiciously monitored for resistance. Prolonged intravenous GCV exposure increases the risk for development of drug resistance. Therefore, precise guidelines are required for prevention of long-term GCV/VGCV exposure. Investigation regarding interferon-gamma release assay and adoptive transfer of T cells in diagnosed CMV patients is warranted to improve future prophylactic and management strategies against CMV, with a potential to reduce the requirement for available toxic antiviral drugs.

Maribavir, brincidofovir and letermovir: Efficacy and safety of new antiviral drugs for treating cytomegalovirus infections

Article

Apr 2018

Cytomegalovirus (CMV) infection is a common complication in immunocompromised patients, especially after hematopoietic stem cell or solid organ transplantation. Therapeutic antiviral options [(val)ganciclovir, foscarnet, cidofovir] are still limited and can expose to severe toxicities. Moreover, prolonged antiviral drug exposure and ongoing viral replication are key factors in the development of antiviral drug resistance. After many years of few tangible advances in terms of new antiviral drugs, we are now experiencing an exciting period characterized by a series of phase III clinical trials incorporating three novel agents: maribavir, brincidofovir, and letermovir. This article summarizes the current state of the prevention and treatment of CMV infections as well as data of investigational drugs in clinical development.

Low-dose valganciclovir prohylaxis is efficacious and safe in cytomegalovirus seropositive heart transplant recipients with anti-thymocyteglobulin

Article

Mar 2018

Background: Cytomegalovirus (CMV) remains an important pathogen in solid organ transplant patients. Objective: We executed a hybrid prophylactic and pre-emptive valganciclovir (VGCV) prophylaxis to prevent CMV infection in heart transplant patients with antithymocyteglobulin (ATG) induction and retrospectively evaluated the efficacy and safety of this regimen. Methods: 100 adult heart transplant patients between 2004 and 2010 were included. Recipients with CMV serostatus D+/R- received VGCV 900mg OD for 6 months and 94,2% (81/86) of R+ recipients received a low-dose 450mg OD for 3 months. Blood CMV was monitored untill 3 months after cessation of the prophylaxis. Results: All patients accomplished the prophylaxis. The overall incidence of CMV disease was 4% (4/100) and it was more frequent in D+/R- patients (p=0.001). 3/86 (3,5%) of R+ patients had CMV infection (one CMV disease) while on prophylaxis, 2/3 were still on the original significantly reduced renal dose though. There was one late CMV disease in both D+/R- and R+ groups. Ganciclovir/ VGCV treatment was successful in all patients. Conclusions: The hybrid strategy with low-dose VGCV in R+ patients with ATG was efficient and safe. The good treatment results indicate that the regimen did not lead to a clinically relevant resistance. Optimal renal dosage is essential throughout prophylaxis. This article is protected by copyright. All rights reserved.

Burden of cytomegalovirus disease in solid organ transplant recipients: A national matched cohort study in an inpatient setting

Article

Full-text available

Jun 2017
TRANSPL INFECT DIS

Background: We investigated the impact of early- (E-CMV) and late-onset (L-CMV) cytomegalovirus disease on the probability of graft rejection, graft failure, mortality, and healthcare resource use, following solid organ transplantation (SOT) in France. Methods: A retrospective analysis of data from the French 'Programme de Médicalisation des Systèmes d'Information' database (2007-2011) was conducted to identify SOT recipients who developed CMV disease in an inpatient setting. Recipients were stratifed by time to CMV disease onset: E-CMV (≤3 months), L-CMV-3M (>3-24 months), and L-CMV-6M (>6-24 months). Data were analyzed by comparing recipients with CMV disease or without (controls) in a 1:2 ratio, matched according to age, gender, target organ, and previous/simultaneous occurrence of graft rejection. Graft failure, graft rejection, all-cause in-hospital mortality, and resource utilization (including hospitalization costs) were assessed over 12 months following CMV disease diagnosis. Results: Among 20 473 SOT recipients, 2430 (11.86%) were reported to have CMV disease within 24 months after transplantation. CMV disease was significantly associated with an increased risk of graft rejection and mortality, as indicated by logistic regression analysis. Odd ratios (ORs) for the risk of graft rejection were E-CMV= 1.43; L-CMV-3M=1.50; L-CMV-6M=1.61 (all P <.05), while ORs for mortality were E-CMV=2.85; L-CMV-3M=4.22; L-CMV-6M=4.77 (all P <.0001). Only L-CMV was significantly correlated with a higher risk of graft failure: E-CMV=1.18 (P=.1906); L-CMV-3M=1.77 (P=.0013); L-CMV-6M=3.12 (P <.0001). Hospitalization costs increased by €7078 (range €6270-€22 111), €6523 (range €5328-€10,295), and €6311 (range €5295-€9184) in recipients with E-CMV, L-CMV-3M, and L-CMV-6-M, respectively. Conclusion: This study, based on French national data, demonstrates the considerable burden of CMV disease in SOT recipients, and highlights the importance of developing new strategies to prevent and manage CMV disease and improve clinical outcomes for SOT patients. This article is protected by copyright. All rights reserved.

Drugs for herpesvirus infections

Chapter

Jan 2010

Cytomegalovirus

Chapter

Jun 2011

A 69-year-old man with chronic renal failure due to hypertension and type 2 diabetes mellitus received a kidney allograft from a deceased donor (Fig. 32.1, week 0). The donor and recipient had no detectable Cytomegalovirus (CMV) IgG. The patient was discharged one week after transplant with an immunosuppressive regimen that included thymoglobulin (begun intraoperatively), tacrolimus, mycophenolate mofetil, and prednisone. The patient was readmitted with pulmonary emboli and deep venous thromboses after complaining of dyspnea. During his hospitalization, he complained of abdominal pain (Fig. 32.1, week 5). The presumed diagnosis was CMV hepatitis, based on elevated liver enzymes and plasma CMV DNA of 5.1 log10 copies/mL by real-time PCR (Fig. 32.1). Ganciclovir was administered intravenously to treat the CMV infection. After two weeks of treatment, the hepatitis appeared to be resolving, as demonstrated by diminished AST levels. However, the viremia remained high (Fig. 32.1, week 7, >5.0 log10 copies/mL). The lack of virologic response raised a concern for the emergence of a ganciclovir-resistant strain, but direct sequencing of viral DNA isolated from plasma detected only wild-type virus. The patient was discharged on intravenous ganciclovir and was transitioned to oral valganciclovir when his viral load reached 3.7 log10 copies/mL (Fig. 32.1, week 9). His dose was reduced by half approximately one week later, due to the side effect of diarrhea. His viral load continued to decline but was still detectable (Fig. 32.1, week 11). During routine follow-up one month later (Fig. 32.1, week 15), the level of CMV viremia was noted to have increased tenfold, although no biochemical signs of hepatitis were observed.

Genomic Applications in the Clinical Management of Infectious Diseases

Chapter

Sep 2015

Next-generation sequencing (NGS) approaches to infectious disease diagnosis and monitoring demonstrate significant sensitivity and throughput advantages over conventional sequencing strategies. As NGS technologies become increasingly accessible and affordable, they are likely to become an important component of clinical microbiology testing. Here, we discuss recent studies that have used NGS platforms to address questions with relevance to diagnostic virology, bacteriology, and mycology. We focus on the advances made in the areas of viral drug resistance testing, detection of unknown disease-associated pathogens in clinical specimens, and investigation of microbial population diversity within the human host. We review different sequencing strategies, distinguishing between targeted amplicon sequencing versus whole-genome sequencing (WGS) approaches, and consider the technical and bioinformatics challenges that have emerged. Although NGS holds enormous promise for clinical microbiology, much remains to be accomplished, particularly in regard to standardizing technical protocols and bioinformatics tools, which would be prerequisites for the adoption of NGS methods in diagnostic testing.

Treatment of alpha and beta herpesvirus infections in solid organ transplant recipients

Article

Dec 2016

Introduction: Human herpesviruses frequently cause infections in solid organ transplant (SOT) recipients. Areas covered: We provide an overview of the clinical impact of alpha and beta herpesviruses and highlight the mechanisms of action, pharmacokinetics, clinical indications, and adverse effects of antiviral drugs for the management of herpes simplex virus, varicella zoster virus and cytomegalovirus. We comprehensively evaluated key clinical trials that led to drug approval, and served as the foundation for management guidelines. We further provide an update on investigational antiviral agents for alpha and beta herpesvirus infections after SOT. Expert commentary: The therapeutic armamentarium for herpes infections is limited by the emergence of drug resistance. There have been major efforts for discovery of new drugs against these viruses, but the results of early-phase clinical trials have been less than encouraging. We believe, however, that more antiviral drug options are needed given the adverse side effects associated with current antiviral agents, and the emergence of drug-resistant virus populations in SOT recipients. Likewise, optimized use and strategies are needed for existing and novel antiviral drugs against alpha and beta-herpesviruses in SOT recipients.

Drugs for Herpesvirus Infections

Chapter

Jan 2017

Cytomegalovirus Infection After Solid Organ Transplantation

Chapter

Mar 2012

Cytomegalovirus (CMV) is the single most important pathogen affecting solid organ transplant (SOT) recipients. CMV may occur as a primary infection in CMV-naïve patients after SOT, or it can be reactivation of latent donor or recipient infection in CMV-seropositive SOT recipients. CMV may present as a subclinical infection among SOT recipients with sufficient pathogen-specific immunity, or clinically apparent CMV-induced tissue damage, termed CMV disease, among SOT recipients without sufficient CMV specific immunity (such as CMV D+/R− SOT patients). CMV disease is manifested by fever, malaise, myelosuppression, and/or signs of end-organ involvement. CMV is also associated with numerous indirect effects, such as an increased risk of acute rejection, chronic allograft failure, and other opportunistic infections. Because of its negative impact, CMV prevention is a major focus of posttransplant management, accomplished either by preemptive therapy or antiviral prophylaxis. Treatment of CMV disease is accomplished by the use of intravenous ganciclovir or oral valganciclovir. Reduction in immunosuppression is recommended when dealing with severe cases of CMV disease. Resistance to ganciclovir is emerging, and may be treated with alternative drugs such as foscarnet and cidofovir. Several novel antiviral drugs are currently undergoing clinical trials for prevention and treatment of CMV disease.

Resistant cytomegalovirus in intestinal and multivisceral transplant recipients

Article

Feb 2016
TRANSPL INFECT DIS

Background: Intestinal and multivisceral transplantation can be complicated by cytomegalovirus (CMV)-related viremia and disease. Intravenous ganciclovir (GCV) and oral valganciclovir remain the treatment of choice in this setting. Limited data are available on GCV-resistant (GCV-R) CMV infection in small intestine and multivisceral transplant recipients. Method: A retrospective review was performed on all patients who underwent small intestine or multivisceral transplantation from November 8, 2003 through November 30, 2008. Those with CMV viremia and invasive disease were identified. GCV resistance was suspected in patients who continued to have viremic episodes or invasive disease despite appropriate GCV treatment. Genotypic analyses were performed to detect the presence of GCV resistance genes UL97 and UL54. Results: During the study period, 88 small intestine or multivisceral transplants were performed on 85 patients. Of the 88 transplantations, 16 patients developed CMV viremia with or without end-organ disease (18.2%) and 5.7% developed GCV-R CMV infection. In patients diagnosed with CMV infection, 31.3% (5/16) had GCV-R CMV infection. Of patients with GCV-R CMV infection, 80% (4/5) developed CMV allograft enteritis, resulting in allograft explantation in 3 patients. All patients with GCV-R CMV infection were CMV donor positive/recipient negative. Patients with tissue-invasive CMV disease were 18 times more likely to be infected with GCV-R CMV (95% confidence interval 1.24-260.93; P-value 0.0341). Conclusion: Small intestinal and multivisceral transplant recipients have a higher rate of GCV-R CMV infection compared with other solid organ transplant recipients, which is often associated with tissue-invasive disease and allograft loss. This article is protected by copyright. All rights reserved.

Anti‐HCMV Compounds

Chapter

May 2011

IntroductionAnti-HCMV Drugs in Clinical UseNeed for New Anti-HCMV DrugsNovel Viral TargetsCellular TargetsConclusions References

Traitements antiviraux de l’infection sévère à cytomégalovirus – état des lieux et perspectives

Article

Jan 2016

Cytomegalovirus (CMV) infection is a common complication in immunodeficient patients, especially after haematopoietic stem cell or solid organ transplantation, and it is associated with multiple direct and indirect effects. Universal antiviral prophylaxis and a pre-emptive treatment strategy are options for prevention. However, therapeutic options ([val]ganciclovir, foscarnet, cidofovir) are still limited and could expose to severe toxicities. Moreover, drug-resistant CMV infection is now increasing in incidence. After many years during which we have seen few tangible advances in terms of new antiviral drugs, we are now experiencing an exciting period of late-stage drug development, characterized by a series of phase III trials incorporating a variety of novel agents (especially letermovirir and brincidofovir).This article reviews the current state of treatment of severe CMV infections and summarizes the data on investigational drugs in clinical development.

Current Strategies and Future Directions in Cytomegalovirus (CMV) Pneumonitis

Article

Jul 2009

Exposure-toxicity relationships and pharmacogenetics of ganciclovir in renal transplant patients

Article

Full-text available

Oct 2015

Pierre-André Billat

Les infections par cytomégalovirus sont un problème majeur en transplantation rénale du fait de l’augmentation du risque de perte de greffon et de l’augmentation de la morbi-mortalité des patients. Toutefois la mise en place d’un traitement prophylactique par ganciclovir a significativement fait diminuer l’incidence de ces infections. Cette efficacité est toutefois limitée par une importante hématotoxicité notamment des neutropénies. La survenue de cet évènement indésirable conduit à une réduction des doses voire à un arrêt du traitement, favorisant ainsi l’émergence de résistances virales. Ces résistances sont un problème grandissant chez les personnes transplantées du fait du manque de protocole de prise en charge de celles-ci. Dans ce contexte notre objectif était de mieux comprendre la survenue et le mécanisme de cette toxicité. Dans un premier temps nous avons étudié le métabolisme intracellulaire du ganciclovir chez des patients. Nous avons remarqué qu’il y a une forte corrélation entre l’exposition à la forme active du ganciclovir et la diminution du nombre de neutrophiles au 3ème mois de traitement. Nous avons par la suite étudié l’impact de variations génétiques sur des transporteurs. Nous avons remarqué qu’un polymorphisme était fortement associé à une diminution du nombre de neutrophiles et qu’il entrainait également une augmentation de la concentration intracellulaire de ganciclovir à l’aide d’un modèle in vitro. Cette thèse fournit de nouveaux outils d’exploration du métabolisme et de l’accumulation intracellulaire du ganciclovir qui pourraient être utiles pour la prévention de la survenue de neutropénies sous ganciclovir.

Next-Generation Sequencing for Infectious Disease Diagnosis and Management: A Report of the Association for Molecular Pathology

Article

Oct 2015

Next-generation sequencing (NGS) technologies are increasingly being used for diagnosis and monitoring of infectious diseases. Herein, we review the application of NGS in clinical microbiology, focusing on genotypic resistance testing, direct detection of unknown disease-associated pathogens in clinical specimens, investigation of microbial population diversity in the human host, and strain typing. We have organized the review into three main sections: i) applications in clinical virology, ii) applications in clinical bacteriology, mycobacteriology, and mycology, and iii) validation, quality control, and maintenance of proficiency. Although NGS holds enormous promise for clinical infectious disease testing, many challenges remain, including automation, standardizing technical protocols and bioinformatics pipelines, improving reference databases, establishing proficiency testing and quality control measures, and reducing cost and turnaround time, all of which would be necessary for widespread adoption of NGS in clinical microbiology laboratories.

Investigation of Ganciclovir Resistance in CMV UL54 and UL97 Gene Regions in Immunocompromised Patients Receiving Gancyclovir Treatment

Article

Jul 2015
MIKROBIYOL BUL

Cytomegalovirus (CMV) is a main cause of severe morbidity and mortality in immunocompromised patients. Ganciclovir (GCV) is used for both prophylaxis and treatment of CMV disease with successful results, however GCV resistance has been increasingly reported. The aim of this study was to investigate the GCV resistance in patients whose viral loads did not decline (≥1000 copies/mL) despite of receiving GCV treatment, by using sequence analysis method. A total of 30 patients, 25 of them were bone marrow transplant (BMT) and five who were followed in hematology clinics (non-Hodgkin lymphoma, lung cancer, diffuse large B cell lymphoma, combined immune deficiency, chronic lymphocytic leukemia) were included in the study. CMV-DNA levels were monitored by real-time polymerase chain reaction (QIAsymphony, Artus® CMV QS-RGQ kit, Qiagen, Germany), and DNA sequence analysis (ABI 310 Genetic Analyzer, Applied Biosystems, USA) was performed to detect the mutations leading to CMV antiviral drug resistance in following gene regions: 420-664 codons in UL97 gene region and 261 to 588 and 740 to 987 codons in UL54 gene region. Of 30 patients included, M460V mutation in CMV UL97 gene region was detected in one (3.3%) (1st case) and L802M mutation in UL54 gene region, in addition to P887S and S897L variant sequences in another patient (3.3%) (2nd case). The first patient was a 20-year-old male with acute myeloid leukemia who underwent BMT. The blood sample for the investigation of antiviral drug resistance was taken on the 117th day of transplantation (with simultaneous viral load 4470 copies/mL) and the patient has been using GCV for 70 days when the sample was taken. Valganciclovir (VGCV) and foscarnet (FOS) were used for the therapy of the first patient and monitored. The second patient was a 19-year-old male with acute lymphoblastic leukemia who underwent BMT. The blood sample for the investigation of antiviral drug resistance was taken on the 109th day of transplantation (with simultaneous viral load 4830 copies/mL) and the patient received GCV for 26 days and VGCV for 40 days when the sample was taken. FOS and cidofovir were used for the therapy of the second patient but the patient was lost due to the underlying diseases. In conclusion, mutations responsible for GCV resistance was detected in 6.6% (2/30) of immunocompromised patients receiving GCV, indicating that the determination of CMV antiviral drug resistance may help clinicians for planning the antiviral therapy.

Cytomegalovirus in immunocompromised children

Article

Jun 2015
CURR OPIN INFECT DIS

The purpose of this study is to explore the latest developments in the risk factors, prevention and treatment of cytomegalovirus (CMV) infection in immunocompromised children, including those with congenital immunodeficiency or iatrogenic immune suppression related to solid organ transplantation (SOT) or haematopoietic cell transplantation (HCT). CMV viral load measurements now have international standards, allowing for more reliable comparison across sites and within individuals. Preemptive and prophylactic therapy with routine CMV monitoring in transplant patients has yielded significant reduction in CMV morbidity and mortality in these patients. The majority of U.S. states have adopted routine newborn screening for severe combined immunodeficiency (SCID). Viral infections, including CMV, are a major obstacle preventing optimal curative transplantation in these patients. Several new antiviral agents are currently being investigated for CMV infection in immunocompromised patients. Knowledge on CMV drug resistance in children is emerging and requires further study. Conditions that diminish cell-mediated immunity impact the development of CMV infection and disease. These conditions include certain congenital immunodeficiencies and SOT and HCT. Infants identified as having SCID should be screened for CMV risk factors. A preemptive or prophylactic strategy should be chosen for CMV management in children who are high risk posttransplantation. In those who develop disease, viral loads should be monitored and resistance testing considered if response is not deemed adequate. Oral valganciclovir is being used as an alternative to ganciclovir in children, although pharmacokinetic data are limited. Other oral antiviral agents under development are promising future options for paediatric CMV therapy.

Drug-resistant cytomegalovirus in transplant recipients: a French cohort study

Article

Dec 2010

Objectives: Cytomegalovirus (CMV) drug resistance is a therapeutic challenge in the transplant setting. No longitudinal cohort studies of CMV resistance in a real-life setting have been published in the valganciclovir era. We report findings for a French multicentre prospective cohort of 346 patients enrolled at initial diagnosis of CMV infection (clinical trial registered at clinicaltrials.gov: NCT01008540). Patients and methods: Patients were monitored for detection of CMV infection for ≥2 years. Real-time detection of resistance by UL97 and UL54 gene sequencing and antiviral phenotyping was performed if viral replication persisted for >21 days of appropriate antiviral treatment. Plasma ganciclovir assays were performed when resistance was suspected. Results: Resistance was suspected in 37 (10.7%) patients; 18/37 (5.2% of the cohort) had virological resistance, associated with poorer outcome. Most cases involved single UL97 mutations, but four cases of multidrug resistance were due to UL54 mutations. In solid organ transplant recipients, resistance occurred mainly during primary CMV infection (odds ratio 8.78), but also in two CMV-seropositive kidney recipients. Neither CMV prophylaxis nor antilymphocyte antibody administration was associated with virological resistance. Conclusions: These data show the feasibility of surveying resistance. Virological resistance was frequent in patients failing antiviral therapy. More than 1/5 resistant isolates harboured UL54 mutations alone or combined with UL97 mutations, which conferred a high level of resistance and sometimes were responsible for cross-resistance, leading to therapeutic failure.

Human Cytomegalovirus Infection in Solid-Organ Transplantation

Article

Full-text available

Jan 2015

Yong-Hee Kim

Human cytomegalovirus (CMV) continues to be a major threat against solid-organ transplant recipients despite significant advancements in its prophylaxis and therapy. Primary CMV infection or reactivation of latent CMV in the transplant recipients may cause CMV diseases such as flu-like viral syndrome and tissue-invasive CMV disease. In addition, CMV infection in the recipients is associated with graft rejection and higher risk of other opportunistic infections, which are collectively known as the "indirect effects" of CMV infection. Prevention strategies with antiviral drugs including ganciclovir remarkably decreased CMV disease and the "indirect effects". Two commonly employed strategies are universal prophylaxis and preemptive therapy. However, gangciclovir-resistant CMV has emerged due to mutations in CMV UL97 and UL54 genes, now requiring alternative therapeutic options to be developed. This review provides an overview of CMV infection and disease, "indirect effects" on hosts, prevention strategies, and drug resistance in solid-organ transplant recipients.

Impact of Cytomegalovirus on Long-Term Mortality and Cancer Risk After Organ Transplantation

Article

Feb 2015

There is conflicting evidence of the effect of cytomegalovirus (CMV) infection on survival and the risk of cancer after transplantation. All recipients of kidney, liver, heart, and lung transplants in the United Kingdom between 1987 and 2007 with known CMV immunoglobulin G status were identified from the U.K. Transplant Registry. Based on the donor-recipient CMV status, recipients were grouped into: donor (D) negative recipient (R) negative (D- R-), D-R+, D + R+ and D + R-. Cancer data were obtained from the Office for National Statistics. The impact of CMV infection on survival and cancer incidence was assessed. The 10-year posttransplant survival in D-R- recipients (73.6% [95%CI, 72.3, 74.9]) was significantly higher (P < 0.0001) than in other recipients (66.1% [65.3, 66.9]). Compared with the D- R- group, the risk-adjusted hazard of death within 10 years of transplantation for D+ R- group was 14% higher for kidney recipients (P = 0.0495), 13% higher for liver recipients (P = 0.16), 34% higher for heart recipients (P = 0.01), and 35% higher for lung recipients (P = 0.006). The proportion of recipients with a cardiovascular cause of death was higher (P = 0.03) among the recipients exposed to CMV (18%) as compared to the D- R- recipients (16%). The CMV status was not associated with an increased risk of cancer. The results from this large study demonstrate that CMV is associated with a significantly increased long-term mortality in kidney and cardiothoracic transplant recipients and an increased risk of cardiovascular death but not of posttransplant cancer.

Cytomegalovirus Infection in Liver Transplant Recipients

Article

Jan 2012

Cytomegalovirus (CMV) is one of the most common opportunistic infections in liver transplant recipients and has significant impact on patient outcomes. A number of strategies to prevent and treat CMV disease in these patients have been developed, but despite these advances, CMV infection still poses a unique and significant risk to liver transplant recipients. Liver transplant patients provide distinctive challenges, and a significant amount of controversy exists in their management compared to other organ transplant recipients because many studies evaluating the management of CMV are not specific to this population. This article reviews the effect of CMV on liver transplant recipients and the ongoing challenges in treatment and prevention of these complications.

High Incidence of Ganciclovir‐Resistant Cytomegalovirus Infection among Lung Transplant Recipients Receiving Preemptive Therapy

Article

Full-text available

Feb 2002

Preemptive antiviral therapy in transplant patients is thought to be less likely to lead to antiviral resistance than is routine prophylaxis. Cytomegalovirus (CMV)–seropositive lung transplant patients (R+) were assigned to receive pp65 antigen–guided ganciclovir therapy, and seronegative recipients of organs from seropositive donors (D+/R−) were assigned to receive initially preemptive and then routine ganciclovir prophylaxis. The incidence of infection with ganciclovir-resistant (ganR) CMV was assessed retrospectively. GanR CMV infection developed in 4 (9%) of 45 patients, at a median of 4.4 months (range, 3.1–6.6 months) after transplantation, and was more common among D+/R− patients than among R+ patients (3 of 11 vs. 1 of 34; P = .04). The incidence among patients who received preemptive therapy was similar to that among patients who received routine prophylaxis. All ganR isolates contained a UL97 mutation. GanR CMV infection occurs in nearly 10% of lung transplant recipients, despite preemptive antiviral therapy, and is more common among D+/R− patients

Cytomegalovirus Disease in High-Risk Transplant Recipients Despite Ganciclovir or Valganciclovir Prophylaxis

Article

Full-text available

Jul 2003

The clinical patterns and predictors of cytomegalovirus (CMV) disease in kidney and/or pancreas transplant patients on ganciclovir (1.0 g po t.i.d.) or valganciclovir (450 mg po q.d.) prophylaxis were studied. This is a retrospective analysis of 129 transplant recipients. Median follow up was 12 months (range, 6–18 months). The overall incidence of CMV disease at 1-year post-transplant was 14% (4% tissue-invasive, 10% noninvasive). Seventeen of 18 patients were diagnosed with CMV after completion of 3 months' prophylaxis (median 8 weeks, range, 2–28 weeks). Induction treatment with thymoglobulin, and Donor +/Recipient – CMV status were the strongest predictors for the development of CMV disease. Cytomegalovirus incidence was not different between patients treated with ganciclovir or valganciclovir (15 vs. 17%, respectively). Valganciclovir (450 mg q.d.) is as effective as oral ganciclovir in CMV prophylaxis. High-risk individuals might require higher doses or longer duration of valganciclovir treatment.

Efficacy and Safety of Valganciclovir vs. Oral Ganciclovir for Prevention of Cytomegalovirus Disease in Solid Organ Transplant Recipients

Article

Full-text available

May 2004

We compared the efficacy and safety of valganciclovir with those of oral ganciclovir in preventing cytomegalovirus (CMV) disease in high-risk seronegative solid organ transplant (SOT) recipients of organs from seropositive donors (D+/R-). In this randomised, prospective, double-blind, double-dummy study, 364 CMV D+/R- patients received valganciclovir 900 mg once daily or oral ganciclovir 1000 mg three times a day (tid) within 10 days of transplant and continued through 100 days. CMV disease, plasma viremia, acute graft rejection, graft loss and safety were analyzed up to 6 and 12 months post-transplant. Endpoint committee-defined CMV disease developed in 12.1% and 15.2% of valganciclovir and ganciclovir patients, respectively, by 6 months, though with a difference in the relative efficacy of valganciclovir and ganciclovir between organs (i.e. an organ type-treatment interaction). By 12 months, respective incidences were 17.2% and 18.4%, and the incidence of investigator-treated CMV disease events was comparable in the valganciclovir (30.5%) and ganciclovir (28.0%) arms. CMV viremia during prophylaxis was significantly lower with valganciclovir (2.9% vs. 10.4%; p=0.001), but was comparable by 12 months (48.5% valganciclovir vs 48.8% ganciclovir). Time-to-onset of CMV disease and to viremia were delayed with valganciclovir; rates of acute allograft rejection were generally lower with valganciclovir. Except for a higher incidence of neutropenia with valganciclovir (8.2%, vs 3.2% ganciclovir) the safety profile was similar for both drugs. Overall, once-daily oral valganciclovir was as clinically effective and well-tolerated as oral ganciclovir tid for CMV prevention in high-risk SOT recipients.

High-level resistance of cytomegalovirus to ganciclovir is associated with alterations in both the UL97 and DNA polymerase genes (vol 176, pg 69, 1997)

Article

Apr 1998

Registry of the International Society of Heart and Lung Transplantation: twenty-fourth official adult heart transplant report-2007

Article

Jan 2003

The Registry of the International Society for Heart and Lung Transplantation: Twenty-first Official Adult Heart Transplant Report - 2004

Article

Jul 2004
J HEART LUNG TRANSPL

Significance of cytomegalovirus for long-term survival after orthotopic liver transplantation - A prospective derivation and validation cohort analysis

Article

Oct 1998

Background. Cytomegalovirus (CMV) infection and disease has been found to be associated with decreased graft and patient survival among heart transplant recipients. We sought to explore the effect of CMV infection and disease on long-term survival in orthotopic liver transplant (OLT) recipients using a derivation and validation cohort. Methods. For derivation-validation modeling, we used data collected from two prospectively followed cohorts as the basis for multivariate analyses: 167 OLT recipients from the Boston Center for Liver Transplantation (the derivation set; median follow-up: 5.5 years, mortality: 40%) and an independent cohort of 294 OLT recipients from the Mayo Clinic (the validation set; median follow-up: 4.8 years, mortality: 27%). Results. Underlying liver disease other than primary biliary cirrhosis or sclerosing cholangitis, number of units of red blood cells administered during transplantation, and donor CMV seropositivity were the pre- and intratransplant variables independently associated (P<0.01) with decreased long-term survival in the derivation cohort. For variables collected up to 1 year after transplantation, the need for retransplantation, CMV pneumonia, invasive fungal disease, and underlying liver disease other than primary biliary cirrhosis or sclerosing cholangitis were independently associated (P<0.01) with decreased long-term survival in the derivation cohort. The magnitude of the relationship of each pre-, intra-, and posttransplant factor with survival, as measured by the relative risk, did not significantly differ between the derivation and validation cohorts. The derivation model, incorporating pre-, intra-, and posttransplant factors, had receiver operating characteristic areas of 73% and 74% for 5-year mortality in the derivation and validation cohorts, respectively. Conclusions. Data from a derivation and an independent validation cohort demonstrate that CMV factors (reflected by either donor CMV seropositivity at transplantation, CMV pneumonia, or CMV disease within the first posttransplant year) are independently associated with decreased long-term survival in OLT recipients.

A Controlled Trial of Ganciclovir to Prevent Cytomegalovirus Disease after Heart Transplantation

Article

May 1992

Because of the immunosuppression required, heart-transplant recipients frequently have complications caused by cytomegalovirus (CMV), including pneumonia, esophagitis, gastritis, and a syndrome of fever, hepatitis, and leukopenia. We undertook a controlled trial to evaluate the prophylactic administration of ganciclovir to prevent CMV-induced disease after heart transplantation. This randomized, double-blind, placebo-controlled trial was conducted at four centers. Before randomization, the patients were stratified into two groups: those who were seropositive for CMV before transplantation and those who were seronegative but who received hearts from seropositive donors. Ganciclovir was given intravenously at a dose of 5 mg per kilogram of body weight every 12 hours from postoperative day 1 through day 14, then at a dose of 6 mg per kilogram each day for 5 days per week until day 28. Among the seropositive patients, CMV illness occurred during the first 120 days after heart transplantation in 26 of 56 patients given placebo (46 percent), as compared with 5 of 56 patients treated with ganciclovir (9 percent) (P less than 0.001). Among 37 seronegative patients, CMV illness was frequent in both groups (placebo, 29 percent; ganciclovir, 35 percent; P not significant). From day 15 through day 60, the patients who took ganciclovir had significantly fewer urine cultures positive for CMV, but by day 90 there was no difference. More of the ganciclovir-treated patients had serum creatinine concentrations greater than or equal to 221 mumol per liter (2.5 mg per deciliter) (18 percent vs. 4 percent in the placebo group), but those elevations were transient. The prophylactic administration of ganciclovir after heart transplantation is safe, and in CMV-seropositive patients it reduces the incidence of CMV-induced illness.

A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: Heart Rejection Study Group. The International Society for Heart Transplantation

Article

Nov 1990
J Heart Transplant

Cytomegalovirus infection is associated with cardiac rejection and atherosclerosis

Article

Jun 1989

We studied the effects of cytomegalovirus (CMV) infection on 301 cardiac transplant recipients who were treated during the cyclosporine era of immunosuppression (1980 to the present). These patients received varying combinations of cyclosporine, azathioprine, prednisone, rabbit antithymocyte globulin, and OKT3 as their immunosuppressive therapy. Two hundred ten patients were free of CMV infection (non-CMV group). During the same period CMV infection developed in 91 patients, as manifested by a fourfold IgG serologic titer rise, demonstration of CMV inclusion bodies in tissue, or positive cultures for the virus (CMV group). The rate of graft rejection was significantly higher in the CMV group. Graft atherosclerosis was significantly more severe in the CMV group as judged by angiographic criteria or by pathologic study. Patient survival rates were significantly lower in the CMV group. Death caused by graft atherosclerosis was significantly more common among patients in the CMV group. Finally, the graft loss rate (from either death or retransplantation for atherosclerosis) was significantly greater in the CMV group. These data demonstrate that CMV infection in cardiac transplant recipients is associated with more frequent rejection, graft atherosclerosis, and death.

A double-blind placebo-controlled trial of low-dose ganciclovir to prevent cytomegalovirus disease after heart transplantation

Article

Nov 1994
J HEART LUNG TRANSPL

The aim of this double-blind, placebo-controlled study was to determine whether a prolonged course of low-dose ganciclovir prevented the development of clinical cytomegalovirus disease after heart transplantation. Fifty-six consecutive patients were stratified into two groups: cytomegalovirus-positive recipients (n = 40) and cytomegalovirus-negative recipients of organs from cytomegalovirus-positive donors (n = 16). All patients received equine antithymocyte globulin induction for 7 days and maintenance doses of cyclosporine, azathioprine, and prednisolone. Ganciclovir (5 mg/kg intravenously) or matching placebo was given with the premedication, three times weekly for the first 6 weeks after transplantation and for another 2 weeks for each treated rejection episode between 6 and 12 weeks. Ganciclovir prophylaxis reduced the actuarial incidence of cytomegalovirus disease from 71% to 11% in cytomegalovirus-mismatched patients (p < 0.01). Ganciclovir prophylaxis did not reduce the incidence of cytomegalovirus disease in cytomegalovirus-positive recipients (25% in both placebo and ganciclovir groups) but did delay its onset and reduce its morbidity. There were no adverse reactions during ganciclovir administration. Gastritis was the most common clinical manifestation of cytomegalovirus disease. Pneumonitis and myocarditis were seen only in placebo-treated cytomegalovirus-mismatched patients. All patients with clinical cytomegalovirus disease responded to ganciclovir, 10 mg/kg/day for 2 weeks. Prolonged low-dose ganciclovir prophylaxis after heart transplantation reduces the incidence of cytomegalovirus disease in cytomegalovirus-mismatched patients and reduces the morbidity of cytomegalovirus disease in cytomegalovirus-positive recipients.

Preemptive ganciclovir therapy to prevent cytomegalovirus disease in cytomegalovirus antibody-positive renal transplant recipients. A randomized controlled trial

Article

Aug 1995

To determine whether preemptive ganciclovir therapy administered daily during antilymphocyte antibody therapy can prevent cytomegalovirus disease in renal transplant recipients who are positive for cytomegalovirus antibody. Randomized, controlled, multicenter trial. 6 university-affiliated transplantation centers. 113 renal transplant recipients who were positive for cytomegalovirus antibody. Patients were randomly assigned to receive either 1) ganciclovir, 2.5 mg/kg body weight administered intravenously on every day that antilymphocyte antibody therapy was administered or 2) no anticytomegalovirus therapy. Patients were observed for 6 months after completion of antilymphocyte antibody therapy for development of cytomegalovirus disease and cytomegalovirus viremia. Cytomegalovirus disease occurred in 14% of patients (9 of 64) who received preemptive ganciclovir therapy and in 33% of controls (16 of 49) (P = 0.018). Cytomegalovirus was isolated from buffy-coat specimens from 17% of patients (11 of 64) receiving preemptive ganciclovir and from 35% of controls (17 of 49) (P = 0.03). Controlling for the reason (induction or treatment of rejection) for using antilymphocyte antibodies in a Cox proportional hazards model, we found that preemptive ganciclovir still protected against cytomegalovirus disease (adjusted relative risk, 0.27; 95% CI, 0.12 to 0.64). No adverse events were attributed to preemptive ganciclovir therapy during or within 6 months of its administration. Preemptive ganciclovir therapy administered daily during courses of treatment with antilymphocyte antibodies reduced the excessive occurrence of cytomegalovirus disease in renal transplant recipients who were positive for cytomegalovirus antibody. This approach, which links the most potent immunosuppression to intensive antimicrobial therapy, allows preventive therapy to be given to those patients at greatest risk for developing infectious complications. These patients are likely to benefit most from the preventive strategy.

High-Level Resistance of Cytomegalovirus to Ganciclovir Is Associated with Alterations in Both the UL97 and DNA Polymerase Genes

Article

Aug 1997

Mutations in both the viral phosphotransferase gene, UL97, and the DNA polymerase gene, UL54, have been shown to confer ganciclovir resistance to cytomegalovirus (CMV). Moreover, UL54 alterations have been associated with in vitro cross-resistance of CMV to cidofovir. To investigate the relative significance of UL97 versus UL54 alterations in conferring antiviral resistance, phenotypic and genotypic characterization of 28 ganciclovir-resistant clinical CMV isolates was undertaken. Isolates were either low-level ganciclovir-resistant, which have ganciclovir ID50 values ⩾8 µM and <30 µM and sensitivity to cidofovir, or high-level ganciclovir-resistant, which have ganciclovir ID50 values ⩾30 µM and cross-resistance to cidofovir. Low-level ganciclovir-resistant isolates were associated with UL97 alterations and short periods of ganciclovir treatment, while high-level ganciclovir-resistant isolates were associated with both UL97 and polymerase alterations and were cultured after extended ganciclovir therapy.

The impact of ganciclovir-resistant cytomegalovirus infection after lung transplantation

Article

Nov 1999

Cytomegalovirus (CMV) resistance to ganciclovir has become increasingly common in acquired immunodeficiency syndrome patients but has only rarely been reported in recipients of solid organ transplants. A retrospective study of ganciclovir susceptibility testing of CMV isolates recovered from lung transplant recipients was performed. Patients with CMV isolates having partial (1<IC50<3 microg/ml) or full resistance (IC50> or =3 microg/ml) to ganciclovir determined by plaque reduction assay were included in a case-control study to identify risk factors for ganciclovir resistance. Between 2/91 and 5/98, 18 patients (5.2% of patients transplanted) were found to have CMV infections with some degree of ganciclovir resistance (4 partially, 14 fully resistant). More positive viral blood cultures (3.2+/-2.5 vs. 1.6+/-1.4 CMV positive cultures, P=0.02) and more episodes of CMV pneumonitis (0.24+/-0.23 vs. 0.10+/-0.17 episodes/bronchoscopy, P=0.02) occurring before the detection of resistance were seen among resistant patients than controls. Ganciclovir-resistant patients received more antithymocyte globulin during induction (70+/-44 vs. 45+/-39 mg/kg, P=0.03) and received ganciclovir for a greater number of days (79+/-52 vs. 64+/-53 days, P=0.005) before the detection of resistance than controls. Ganciclovir-resistant patients had a shorter survival and an earlier onset of bronchiolitis obliterans syndrome compared with patients in the transplant database at Washington University. Ganciclovir-resistant CMV infection is a serious complication of solid organ transplantation associated with more episodes of viremia, more frequent disease, earlier onset of bronchiolitis obliterans and shorter survival. The use of antithymocyte globulin and prolonged exposure to ganciclovir are risk factors for the development of ganciclovir resistance.

Prevention and treatment of cytomegalovirus disease in heart transplant patients

Article

Sep 2000
J HEART LUNG TRANSPL

Robert H. Rubin

Cytomegalovirus (CMV) remains the most important infection affecting heart-transplant recipients. Treatment of clinical disease is with a two to three-week course of intravenous ganciclovir, which is effective in more than 90% of individuals. However, relapsing disease, particularly in those with primary infection, is an increasing problem, occasionally with the development of ganciclovir-resistant infection. In those instances, foscarnet is needed, despite its nephro- and neurotoxicities. Increasingly, in order to prevent relapse, more prolonged oral courses of anti-viral therapy are being added to the standard two to three-week course of intravenous treatment. In the prevention of CMV disease, those at risk of primary disease (donor seropositive, recipient seronegative) should receive prophylaxis; for seropositive transplant patients, preemptive strategies linked to immunosuppression or viremia monitoring are becoming increasingly prevalent. In the future, as new drugs become available, the essential question will be whether chronic allograft injury (i.e., accelerated coronary artery atherosclerosis) can be prevented with an anti-viral strategy.

Emergence of ganciclovir-resistant cytomegalovirus disease among solid organ transplant (SOT) recipients.

Article

Sep 2000

Concerns have been raised about emergence of ganciclovir resistance as a result of the advent of both routine oral ganciclovir prophylaxis and highly potent immunosuppression. We retrospectively assessed the occurrence of ganciclovir-resistant cytomegalovirus disease among transplant recipients who had received oral ganciclovir prophylaxis and highly potent immunosuppression. We studied 240 recipients of liver, kidney, or pancreas transplants. Antiviral susceptibility testing of blood cytomegaloviral isolates was done when patients failed to respond to intravenous ganciclovir treatment for symptomatic cytomegalovirus infection. Portions of the UL97 gene associated with ganciclovir resistance were sequenced in cytomegalovirus isolates with phenotypic resistance to ganciclovir. Ganciclovir-resistant cytomegalovirus disease developed in five (7%) of 67 seronegative recipients of cytomegalovirus-seropositive organs (D+/R-) compared with none of 173 seropositive recipients (p=0.002). Among the 25 (10.4%) patients who developed cytomegalovirus disease within 1 year after transplantation, five had ganciclovir-resistant cytomegalovirus disease. Among D+/R-transplant recipients, ganciclovir-resistant cytomegalovirus disease was more common among the group receiving the most potent immunosuppression--ie, recipients of kidney and pancreas or pancreas alone (four of 19) compared with all other transplant recipients (one of 48, p=0.02). Ganciclovir-resistant cytomegalovirus disease was diagnosed at a median of 10 months after transplantation (range 7-12) after lengthened exposure to ganciclovir, was associated with previously described mutations of the UL97 gene, and led to serious clinical complications. Ganciclovir-resistant cytomegalovirus is an important cause of late morbidity among D+/R- transplant recipients who have had lengthened exposure to ganciclovir and have received highly potent immunosuppression. Strategies to reduce this complication, especially among D+/R- patients, are warranted.

Prevention of primary cytomegalovirus disease in organ transplant recipients with oral ganciclovir or oral acyclovir prophylaxis

Article

Sep 2000

Optimal prophylaxis against cytomegalovirus (CMV) disease for organ transplant patients at risk for primary infection (donor seropositive, recipient seronegative, D+R-) remains to be determined. We hypothesized that prolonged oral ganciclovir therapy following intravenous therapy would provide increased protection. A total of 155 evaluable D+R- organ transplant recipients from 13 transplant centers were entered into the study: all received intravenous ganciclovir (5 mg/kg/day) for 5-10 days and then either oral acyclovir (400 mg tid) or oral ganciclovir (1 g tid) for an additional 12 weeks. Patients were assigned to their treatment groups at a central randomization site, with a separate randomization scheme for each of the organs transplanted (kidney, heart, or liver). In the case of kidney transplants, the patients were stratified according to source of the kidney (living related vs. cadaveric donor). The primary endpoint was the incidence of CMV disease in the first six months post-transplant. Treatment with oral ganciclovir was associated with a significant decrease in the incidence of symptomatic disease or viremia when compared with the oral acyclovir group (32% vs. 50%, P<0.05). This difference was most marked in terms of tissue invasive disease: only 3 of 15 symptomatic patients in the ganciclovir group vs. 10 of 21 in the acyclovir group developed tissue-invasive infection (P<0.05). There was a significant difference in the time to CMV disease or viremia in the two groups: mean time 212+/-17 days post-transplant for the acyclovir group vs. 291+/-13 days for the ganciclovir group (P<0.001). The incidence of allograft rejection was 34% in the ganciclovir group and 46% in the acyclovir group (P=NS). Leukopenia was more common in the ganciclovir group (P<0.05), but in no case did it require drug discontinuation. Ganciclovir resistance did not develop in this study. Prophylaxis with oral ganciclovir following a brief course of intravenous ganciclovir provides useful protection against primary CMV disease.

Ljungman P, Griffiths P, Paya C. Definitions of cytomegalovirus infection and disease in transplant recipients. Clin Infect Dis 34(8): 1094

Article

May 2002
CLIN INFECT DIS

Cytomegalovirus (CMV) infection and disease are important causes of morbidity and mortality among transplant recipients. For the purpose of developing consistent reporting of CMV in clinical trials, definitions of CMV infection and disease were developed and published. This study seeks to update the definitions of CMV on the basis of recent developments in diagnostic techniques, as well as to add to these definitions the concept of indirect effects caused by CMV.

Limaye, A. P. Ganciclovir-resistant cytomegalovirus in organ transplant recipients. Clin. Infect. Dis. 35, 866-872

Article

Nov 2002
CLIN INFECT DIS

Ajit P Limaye

Ganciclovir-resistant (GanR) cytomegalovirus (CMV) is an emerging clinical problem in organ transplant recipients, particularly recipients of kidney and pancreas and lung transplants. GanR CMV, a late posttransplantation complication, is observed predominantly among CMV-seronegative recipients of organs from seropositive donors, especially among recipients receiving intensive immunosuppression and having prolonged exposure to ganciclovir. Given the limitations of current diagnostic methods, if GanR CMV is clinically suspected, empirical treatment with intravenously administered foscarnet should be used in conjunction with reductions in immunosuppressive therapy and possibly CMV hyperimmune globulin. Better diagnostic tools and newer, less-toxic antiviral agents with different mechanisms of action are urgently needed to decrease the morbidity associated with this complication in organ transplant recipients.

Emergence of ganciclovir-resistant cytomegalovirus in lung transplant recipients

Article

Jan 2003
J HEART LUNG TRANSPL

Since ganciclovir-resistant cytomegalovirus (CMV) disease was initially described in a patient with acquired immunodeficiency syndrome (AIDS) in 1986, the incidence of ganciclovir-resistant CMV disease appears to be increasing in immunocompromised patients. More recently, there have been sporadic reports of ganciclovir-resistant CMV disease in solid organ transplantation. We retrospectively assessed the incidence of ganciclovir-resistant CMV disease in all lung transplant recipients transplanted between 6/93 and 6/01 at Loyola University Medical Center. All patients underwent routine CMV blood culture, shell vial assay as well as phenotypic and genotypic anti-viral susceptibility testing according to a pre-determined schedule. The number of CMV episodes, intravenous ganciclovir use, acute and chronic rejection and survival data were documented for all patients. Twelve of 212 (6%) transplant recipients developed ganciclovir-resistant CMV disease. Ganciclovir resistance was associated with a higher number of CMV episodes (3.4 +/- 2.3 episodes/patient vs 1.7 +/- 0.7 episodes/patient [p < 0.05]) and an increased exposure to cumulative intravenous ganciclovir in the primary CMV-mismatched (D(+)R(-)) population (22 +/- 10 vs 13 +/- 7 days [p < 0.05]) compared with patients who did not develop ganciclovir resistance. In addition, the use of daclizumab therapy was associated with a 7-fold greater likelihood of developing ganciclovir resistance (p < 0.0001). The presence of ganciclovir-resistant CMV disease in our population was associated with a decreased survival that could be attributed to CMV disease itself (p < 0.05). By screening all lung transplant recipients with CMV disease for ganciclovir resistance, we were able to detect a higher incidence of ganciclovir-resistant CMV disease (6%) than previously seen in solid organ transplantation. High-risk patients (D(+)R(-) CMV serostatus) who receive anti-lymphocytic therapy should be monitored aggressively and treated to prevent the development of ganciclovir resistance and avert a negative outcome.

Antiviral resistance in cytomegalovirus: An emerging problem in organ transplant recipients

Article

Jan 2003
Semin Respir Infect

Ajit P Limaye

In the era of more aggressive immunosuppressive regimens and antiviral prophylaxis, ganciclovir-resistant cytomegalovirus (CMV) has been recognized as an important clinical problem in organ transplant recipients. Among the various solid-organ transplant (SOT) recipients, lung transplant recipients appear to be disproportionately affected. Ganciclovir-resistant CMV appears to be a relatively late posttransplant complication and is seen predominantly among CMV-seronegative recipients of organs from seropositive donors, particularly in the setting of potent immunosuppression and prolonged exposure to ganciclovir (especially oral ganciclovir). Limitations in current diagnostic methods mandate a high clinical index of suspicion. In high-risk patients in whom ganciclovir resistance is clinically suspected, while awaiting laboratory confirmation of resistance, empiric addition of intravenous foscarnet, often combined with reduction in immunosuppression and CMV hyperimmune globulin, are commonly used. Better diagnostic tools and newer, less toxic, antiviral agents with different mechanisms of action are urgently needed to decrease the morbidity associated with this complication in organ transplant recipients.

Viral DNA Polymerase Mutations Associated with Drug Resistance in Human Cytomegalovirus

Article

Aug 2003

Certain mutations in the viral DNA polymerase (pol) gene are known to confer drug resistance when transferred to susceptible human cytomegalovirus (CMV) strains, whereas other putative resistance mutations remain unproven. A new marker-transfer technique was used to produce recombinant CMV strains, to determine the drug susceptibility phenotypes conferred by 10 pol mutations (9 observed in clinical isolates). Various degrees of resistance to ganciclovir and cidofovir were conferred by mutations D301N, N410K, D413E, T503I, and L516R, which are located within exonuclease functional domains where D301N and D413E affect highly conserved residues. Mutations A692S, E756K, and E756D, which are not located within recognized functional domains, each conferred foscarnet resistance. This study significantly increases the number of confirmed CMV pol resistance mutations, at both conserved and nonconserved loci, with implications for molecular mechanisms and the genotypic diagnosis of antiviral resistance.

Impact of early cytomegalovirus infection and disease on long-term recipient and kidney graft survival

Article

Jul 2004

The impact of cytomegalovirus (CMV) infection and disease on long-term outcome after kidney transplantation is still unsettled. Between 1994 and 1997, 397 consecutive first kidney graft recipients and 74 retransplants were included in the study and followed prospectively until December 31, 2001. CMV infection (CMV pp65 antigenemia) and CMV disease were recorded once weekly during the first 100 days after transplantation. No CMV prophylaxis or preemptive therapy was given. In a multiple Cox proportional hazard model allowing time-dependent covariates, the effects of asymptomatic CMV infection and CMV disease, recipient age and gender, retransplantation, living donor, panel-reactive cytotoxid antibodies, acute rejection, and graft loss were tested on overall mortality beyond 100 days post-transplantation. In a similar analysis, the effect of asymptomatic CMV infection and CMV disease plus other factors were tested on death censored graft loss beyond 100 days. Median (range) follow up time was 66.6 (<1-86.9) months. The incidence of CMV infection and disease during the first 100 days was 62.8% and 23.4%, respectively. The number of total deaths was 96 (20%), 82 occurred after the first 100 days. Independent risk factors for overall mortality beyond 100 days were asymptomatic CMV infection, RR = 2.90 (95% CI 1.61-5.22) (P= 0.001), CMV disease, RR = 2.50 (95% CI 1.31-4.79) (P= 0.006), both compared to no infection or disease, recipient age, RR = 1.066 per year (95% CI 1.048-1.084) (P < 0.001), and graft loss in the whole study period RR = 7.88 (95% CI 4.75-13.08) (P < 0.001). Asymptomatic CMV infection and CMV disease were not independent risk factors for death censored graft loss, but they significantly reduced graft survival uncensored for death, (log rank P= 0.001, respectively). Asymptomatic CMV infection and overt CMV disease during the first 100 days increase the risk of recipient mortality beyond 100 days. This raises the question whether CMV prophylaxis should be given routinely after kidney transplantation.

Current outcomes following heart transplantation

Article

Feb 2004
Semin Thorac Cardiovasc Surg

Survival after cardiac transplantation has improved progressively since its inception over 35 years ago, with current 1 year survival approaching 90% and 7 year survival approaching 75%. In view of continued severe donor shortages, allocation must balance the survival benefit margin for recipients with terminal heart failure (higher risk for death with multiple co-morbidities and refractory low output state) and the charge to maximize graft survival. Continued improvement in short and longer-term survival will depend on an understanding of the early and late risk factors after cardiac transplantation and the development of methods and treatments to neutralize them. Specific risk factors vary for the specific causes of mortality, which include primarily early graft failure, infection, and rejection during the first post transplant year; and allograft vasculopathy and malignancy in later years. Evolving trends in risk profiles and survival indicate that patients undergoing cardiac transplantation have experienced a gradual increase in risk profile over the past decade, and have improved survival. Patient-specific risk profiling will play an increasing role in the allocation of transplantation and other emerging therapies for patients with advanced heart failure.

Antiviral medications to prevent cytomegalovirus disease and early death in recipients of solid-organ transplants: A systematic review of randomised controlled trials

Article

Jun 2005
LANCET

Antiviral prophylaxis is commonly used in recipients of solid-organ transplants with the aim of preventing the clinical syndrome associated with cytomegalovirus infection. We undertook a systematic review to investigate whether this approach affects risks of cytomegalovirus disease and death. Randomised controlled trials of prophylaxis with antiviral medications for cytomegalovirus disease in solid-organ-transplant recipients were identified. Data were combined in meta-analyses by a random-effects model. Compared with placebo or no treatment, prophylaxis with aciclovir, ganciclovir, or valaciclovir significantly reduced the risks of cytomegalovirus disease (19 trials, 1981 patients; relative risk 0.42 [95% CI 0.34-0.52]), cytomegalovirus infection (17 trials, 1786 patients; 0.61 [0.48-0.77]), and all-cause mortality (17 trials, 1838 patients; 0.63 [0.43-0.92]), mainly owing to lower mortality from cytomegalovirus disease (seven trials, 1300 patients; 0.26 [0.08-0.78]). Prophylaxis also lowered the risks of disease caused by herpes simplex or zoster virus, bacterial infections, and protozoal infections, but not fungal infection, acute rejection, or graft loss. Meta-regression showed no significant difference in the risk of cytomegalovirus disease or all-cause mortality by organ transplanted or cytomegalovirus serostatus; no conclusions were possible for cytomegalovirus-negative recipients of negative organs. In trials of direct comparisons, ganciclovir was more effective than aciclovir in preventing cytomegalovirus disease. Valganciclovir and intravenous ganciclovir were as effective as oral ganciclovir. Prophylaxis with antiviral medications reduces the risk of cytomegalovirus disease and associated mortality in recipients of solid-organ transplants. This approach should be used routinely in cytomegalovirus-positive recipients and in cytomegalovirus-negative recipients of organs positive for the virus.

Registry of the International Society for Heart and Lung Transplantation: Twenty-second Official Adult Heart Transplant Report—2005

Article

Sep 2005
J HEART LUNG TRANSPL

Clinical impact of ganciclovir-resistant cytomegalovirus infections in solid organ transplant patients

Article

Sep 2005

Clinical consequences of ganciclovir resistant cytomegalovirus (CMV) infections were studied during 2 large prophylactic trials consisting of 100 days of valganciclovir or ganciclovir prophylaxis in solid organ transplant (SOT) recipients. The first one involved 301 high-risk (CMV donor seropositive/recipient seronegative) SOT recipients excluding lung transplants followed for 12 months, whereas the second one involved 80 lung transplant patients evaluated over 6 months. Among the 7 patients (4 non-lung and 3 lung transplant patients) carrying viruses with known ganciclovir-resistance [corrected] mutations in blood, adverse clinical outcome was only observed in the lung transplant recipients. Additionally, no CMV resistance mutations were observed in non-lung transplant patients receiving valganciclovir.

Impact of Cytomegalovirus in Organ Transplant Recipients in the Era of Antiviral Prophylaxis

Article

Jul 2006

Antiviral prophylaxis has been shown to decrease the incidence of cytomegalovirus (CMV) disease in organ transplant recipients, but whether CMV disease that occurs despite prophylaxis is associated with mortality remains unknown. The clinical features and risk factors for CMV disease in a cohort of liver transplant recipients who received antiviral prophylaxis were assessed retrospectively. Cox proportional hazard regression was used to assess the relationship of CMV to mortality during the first posttransplant year. CMV disease developed in 37 of 437 (8.5%) recipients at a median of 4.5 (range, 2.5 to 12) months posttransplant and was associated only with donor-seropositive/recipient-seronegative serostatus in multivariate analysis (P<0.0001). Mortality at 1 year was 12% (51 of 437) and was infection-associated in 49% of cases. In multivariate analysis, CMV disease was independently associated with overall mortality at 1 year (HR, 5.1, P=0.002) and even more strongly with infection-associated mortality (HR 11, P=0.002). There was no association of CMV with noninfection-associated mortality (P>0.05). Late CMV disease is an important clinical problem in liver transplant recipients who receive antiviral prophylaxis, and is strongly and independently associated with mortality. Strategies to prevent late CMV disease are warranted.

Definitions of cytomegalovirus in- Ganciclovir-Resistant CMV and OHT @BULLET CID

Sep 2007
45

P Ljungman
P Griffiths
C Paya

Ljungman P, Griffiths P, Paya C. Definitions of cytomegalovirus in- Ganciclovir-Resistant CMV and OHT @BULLET CID 2007:45 (15 August) @BULLET 447

fection and disease in transplant recipients

Jan 2002
CLIN INFECT DIS
1094-1097

fection and disease in transplant recipients. Clin Infect Dis 2002; 34: 1094-7.

Definitions of cytomegalovirus in-Ganciclovir-Resistant CMV and OHT • CID

Aug 2007
447

P Ljungman
P Griffiths
C Paya

Ljungman P, Griffiths P, Paya C. Definitions of cytomegalovirus in-Ganciclovir-Resistant CMV and OHT • CID 2007:45 (15 August) • 447

Incidence and Clinical Features of Ganciclovir- Resistant Cytomegalovirus Disease in Heart Transplant Recipients

Abstract

No full-text available

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