Ganciclovir-resistant Cytomegalovirus Research Articles

Comparison of prophylaxis and preemptive strategy as cytomegalovirus prevention in liver transplant recipients.

Prophylaxis (P) or pre-emptive strategy (PS) in high-risk liver transplant recipients (LTRs) are either recommended. We compared the results of each strategy. Two groups of LTR transplanted during two consecutive periods were compared. Only cytomegalovirus (CMV)-mismatched LTR (Donor +/ Recipient -) were included. The primary endpoints were: the onset of polymerase chain reaction-based DNAemia and the proportion of patients with CMV disease. A number of episodes of CMV infection, antiviral therapy, ganciclovir resistance, infectious or immunological complications, cost of both strategies, and survival (1, 5, and 10 years) were also compared. Forty-eight and 60 patients were respectively included in the P and PS groups. Eighteen (38%) in the P group and 56 (93%) in the PS group had CMV DNAemia (p <.0001) with a similar CMV disease rate (16.7% and 15%). Duration of curative therapy was longer in the PS group: 91 days versus 16 (p <.0001). Acute rejection was less frequent (p=.04) and more patients experienced a ganciclovir-resistant CMV infection in the PS group (10% vs. 0, p=.03). The drug-associated cost of PS was higher (10 004vs. 4804€) and the median number of rehospitalization days tended to be higher (6vs. 4, p=.06). Survival at any time was similar. We reported more CMV DNAemias and ganciclovir-resistant CMV events with PS. The cost of the PS strategy was higher.

Successful resolution of ganciclovir-resistant cytomegalovirus (CMV) retinitis with intravitreal foscarnet in a seronegative patient of psoriasis on immunosuppressive therapy

We report an unusual case of intravitreal ganciclovir-resistant cytomegalovirus (CMVR) retinitis in a patient with psoriasis taking immunosuppressant medications, who responded to intravitreal foscarnet. A 37-year-old male patient presented with signs of CMVR (dense vitritis, retinal necrosis, and intra-retinal hemorrhages). He was resistant to treatment with intravitreal ganciclovir but responded well to intravitreal foscarnet. He was followed up for 4 months, and complete resolution of the lesion with improvement of vision was observed. Management of ganciclovir-resistant CMVR is challenging, intravitreal foscarnet is effective in such cases.

A New Duplication in 668 to 672 Sites of UL54 Gene in Cytomegalovirus Ganciclovir Resistant Liver Transplanted Patients

Background: In liver transplant recipients, human Cytomegalovirus (CMV) infection is a significant concern. Ganciclovir is the preferred medication for treating widespread CMV infections. In some cases, patients might require high doses of treatment for CMV infections that are resistant to ganciclovir, although liver transplant patients who have received extended ganciclovir and valganciclovir prophylaxis have reported infrequent cases of ganciclovir-resistant CMV infections. Mutations in the UL54 gene, responsible for encoding deoxyribonucleic acid (DNA) polymerase, can result in resistance. Objectives: In this study, the focus was on UL54 mutations and their association with ganciclovir resistance. Methods: In this study, 23 liver transplant recipients who were admitted to the transplant departments of Namazi and Abu Ali Sina hospitals were examined. Cytomegalovirus infection was then confirmed in them using the quantitative real-time polymerase chain reaction (PCR) method. The UL54 mutations were found after electrophoresis using the nested PCR method, and the PCR products were subsequently sequenced using the Sanger method. Sequence analysis and locating of UL54 mutations were performed using Finch software (version 1.4.0). Results: After sequencing 52 samples from 23 patients, 25 mutations in the UL54 gene were identified in 9 patients who were CMV-infected, occurring at a median of 32 days after transplant. These mutations, including S655L (10/9, 40%), N685S (8/9, 32%), F669L (4/9, 16%), A688V (2/9, 8%), and the novel AK124703.1: p.V668-G672dup (1/9, 4%), were detected in 9 liver transplant recipients over a median period of 2 years in the UL54 gene. Furthermore, a phylogenetic analysis was conducted to investigate the origins of these mutations in CMV isolated from the Iranian population. Conclusions: Considering that treatment with the drug ganciclovir has led to resistance mutations, particularly the new AK124703.1:p.V668-G672dup mutation, and inefficiency in treatment, it is necessary to determine drug-resistant CMV strains and closely monitor these patients. This includes determining viral load, assessing response to treatment, and identifying non-response at regular intervals until the viral load is completely eradicated in order to ensure the effectiveness of the treatment.

The next frontier: cytomegalovirus antiviral stewardship programs in solid organ transplant.

Cytomegalovirus (CMV) is a driver of negative patient and allograft outcomes after solid organ transplantation (SOT) and new tools are needed to circumvent these outcomes. We will review key elements of CMV antiviral stewardship in SOT, discuss the available evidence for CMV antiviral stewardship programs and feature areas for expansion in the current landscape of CMV management. CMV remains a common complication after SOT. While consensus guidelines provide recommendations for the prevention and treatment of CMV, a one-size-fits-all approach is not necessarily appropriate for all unique patients and posttransplant courses, types of SOT recipients and transplant centers. Additionally, consensus guidelines have not been updated since the approval of two new antiviral therapies for the treatment of CMV after SOT or emerging evidence for the incorporation of immune functional assays into clinical practice.From the models provided in recent literature, CMV antiviral stewardship programs have demonstrated efficacy by increasing successful treatment of viremia, optimizing and reducing unnecessary use of (val)ganciclovir for both prophylaxis and treatment, and preventing development of ganciclovir-resistant CMV infections. These models highlight the multidisciplinary approach required of CMV antiviral stewardship programs to provide standardization of management, including incorporation of new therapies and diagnostic tools. CMV antiviral stewardship programs represent a promising avenue to considerably improve the management of CMV after SOT. Future studies are needed to evaluate a potential positive impact on graft outcomes and patient survival.

Investigation of Ganciclovir Resistance in Cytomegalovirus Isolates by Phenotypic and Genotypic Methods

Ganciclovir-resistant cytomegalovirus (CMV) strains are reported following long-term antiviral agent use, especially for immune-suppressive patients. In this study, it was aimed to investigate the mutations in the UL97 gene of CMV, which causes ganciclovir (GCV) resistance by genotypic and phenotypic methods in patients who developed CMV infection following hematopoietic cell (HCT) or solid organ transplantation (SOT). Thirty patients who had HCT or SOT in Mediterranean University Hospital and developed CMV infection during routine follow-up with a viral load of CMV over 1000 copies/mL were included in the study. CMV DNA was analyzed by an automated system (Cobas Ampliprep/COBAS TaqMan CMV Test, Roche Diagnostics, Germany) quantitatively. DNA sequence analysis of the regions including codons 420-664 in the UL97 gene region was done by the Sanger sequencing method to detect mutations causing antiviral resistance and compared with defined mutations. In order to investigate antiviral resistance by phenotypic methods, heparinized blood samples of the patients were collected, 'buffy coat (leukocyte layer)' was inoculated into MRC-5 cells by centrifugation method and CMV growth in these cells was controlled with monoclonal antibodies when growth was detected, virus titer was determined and plaque reduction test was applied as recommended. It was determined that 22 of the 30 patients were HCT recipients and eight were SOT (five kidney, three liver) recipients. When the CMV serology pattern of the patients was evaluated before transplantation, 29 (96.7%) patients were found to be seropositive and one (3.3%) patient was found to be seronegative. Totally, nine CMV UL97 mutations were detected in seven (23.3%) pediatric patients who had HCT, including six seropositive and one seronegative case. In addition, one mutation (D605E) not known to cause GCV resistance was detected in a seronegative recipient and three previously unidentified mutations were detected (1474T, F499S, V559A) in a seronegative recipient. Five of the mutations defined were UL97 mutations with a defined clinical resistance against GCV in each of the five recipients (C603W, C592G, H520Q, M460V, A594T). In the plaque reduction test using 3 µM, 12 µM, 48 µM and 96 µM concentrations of GCV in CMV strains, the IC50 value was determined to be ≥ 8 µM for the five CMV strains, and the phenotypic presence of GCV resistance was shown. Clinical resistance associated with CMV UL97 mutation was detected in five (22.7%) of 22 patients who had HCT. GCV resistance was also demonstrated in these patients by phenotypic methods. No UL97 mutation was detected in the patients who had SOT.

Cytomegalovirus Management in Solid Organ Transplant Recipients: A Pre-COVID-19 Survey From the Working Group of the European Society for Organ Transplantation

Infections are leading causes of morbidity/mortality following solid organ transplantation (SOT) and cytomegalovirus (CMV) is among the most frequent pathogens, causing a considerable threat to SOT recipients. A survey was conducted 19 July–31 October 2019 to capture clinical practices about CMV in SOT recipients (e.g., how practices aligned with guidelines, how adequately treatments met patients’ needs, and respondents’ expectations for future developments). Transplant professionals completed a ∼30-minute online questionnaire: 224 responses were included, representing 160 hospitals and 197 SOT programs (41 countries; 167[83%] European programs). Findings revealed a heterogenous approach to CMV diagnosis and management and, sometimes, significant divergence from international guidelines. Valganciclovir prophylaxis (of variable duration) was administered by 201/224 (90%) respondents in D+/R− SOT and by 40% in R+ cases, with pre-emptive strategies generally reserved for R+ cases: DNA thresholds to initiate treatment ranged across 10–10,000 copies/ml. Ganciclovir-resistant CMV strains were still perceived as major challenges, and tailored treatment was one of the most important unmet needs for CMV management. These findings may help to design studies to evaluate safety and efficacy of new strategies to prevent CMV disease in SOT recipients, and target specific educational activities to harmonize CMV management in this challenging population.

Letermovir treatment for CMV infection in kidney and pancreas transplantation: A valuable option for complicated cases.

Cytomegalovirus (CMV) infection remains a major challenge in solid organ transplantation. Ganciclovir has changed the prognosis, but with the expense of possible viral resistance. New antiviral drugs, such as letermovir, have not been studied sufficiently in kidney and pancreas transplant recipients. We reviewed abdominal organ transplants recipients with CMV infection from the national transplant registry and identified patients treated with letermovir from electronic medical records. We report on letermovir treatment in one kidney and three simultaneous pancreas and kidney (SPK) transplant patients with refractory or ganciclovir-resistant CMV infection (UL54/ UL97 mutation). In SPK patients, persistent leukopenia undermined immunosuppressive and antiviral treatment, favoring life-threatening bacterial infections or ganciclovir resistance. All patients achieved viral clearance after letermovir monotherapy of 1.5-6 months. Letermovir was well tolerated and leukopenia resolved. Adjustments of calcineurin inhibitor doses were challenging. One acute rejection occurred because of under immunosuppression. After the end of treatment, recurrent low-grade CMV-DNAemia was common requiring reinitiating antiviral therapy to achieve viral clearance. To conclude, letermovir was a well-tolerated valuable option for the treatment of refractory or resistant CMV infection in kidney and pancreas transplantation.

Use of letermovir-valganciclovir combination as a step-down treatment after foscarnet for ganciclovir-resistant CMV infection in kidney transplant recipients.

BackgroundLetermovir (LTV) might be an alternative treatment to nephrotoxic foscarnet (FOS) in Ganciclovir (GCV) resistant cytomegalovirus (CMV) infection. However, its efficacy in controlling active CMV viremia is unclear, as it is only approved for CMV prophylaxis in hematopoietic stem‐cell transplantation.MethodsThis case series describes 14 kidney transplant recipients (KTR) with moderate‐level GCV resistant CMV infection, treated by different step‐down strategies after initial FOS therapy: (1) Observation without antiviral follow‐up or switch to valganciclovir (VGCV) (pre‐LTV era), and (2) Switch to LTV±VGCV (LTV era).ResultsOne patient died under FOS. Thirteen patients were followed under step‐down regimens. All but two patients had ongoing CMV viremia when stopping FOS. In pre‐LTV era, 5/9 (56%) experienced a CMV breakthrough > 10 000 IU/ml calling for another course of FOS, as compared to 1/4 (25%) in the LTV era. Addition of VGCV to LTV at low‐level viral breakthrough, addressing a possible developing resistance against LTV, prevented viral surge in two patients. In the pre‐LTV era, CMV‐related death or graft loss occurred in three of nine (33%), compared to no death or graft loss in the LTV era.ConclusionA step‐down strategy combining LTV+VGCV, might allow to safely stop FOS at ongoing low‐level viremia.

A New Viral Coinfection: SARS-CoV-2 Pneumonia and Cytomegalovirus Pneumonitis in a Renal Transplant Recipient

SARS-CoV-2 has caused a global pandemic of an acute respiratory illness known as COVID-19. Patients with solid organ transplants receiving chronic immunosuppressive therapy are at risk of severe disease caused by opportunistic pathogens, including cytomegalovirus (CMV). We present the case of a renal transplant recipient presenting with hypoxic respiratory failure because of severe COVID-19, whose course was complicated by ganciclovir-resistant CMV pneumonitis.

Use of Maribavir and Letermovir for Ganciclovir-Resistant Cytomegalovirus Infection in Lung Transplant Recipients

<h3>Introduction</h3> Cytomegalovirus (CMV) infection is a major contributor to morbidity and mortality in solid organ transplant recipients. Ganciclovir-resistant (gan-R) CMV is an emerging concern associated with potent immunosuppression and increased durations of antiviral exposure. Limited data exists regarding efficacy of maribavir and letermovir for treatment and secondary prophylaxis in resistant CMV. <h3>Case Report</h3> We report a series of 3 lung transplant recipients with gan-R CMV infection treated with maribavir or letermovir between June 1, 2015 and June 1, 2020. Maribavir and letermovir were initiated as monotherapy for CMV treatment in 3 and 1 patients, respectively, with maribavir dosing per institutional study protocol. Patient A was transitioned to letermovir prophylaxis following maribavir treatment. Patient C was transferred to an outside hospital for CMV T-cell therapy and was not discharged on antiviral prophylaxis. Both maribavir and letermovir were well-tolerated by patients. <h3>Summary</h3> Maribavir 200 mg twice daily resulted in CMV viral suppression in one patient. Patients B and C received much shorter durations of maribavir treatment, which may have been associated with delayed quantitative viral reduction as described in the literature, and subsequent transition to alternative therapy. Further research is needed to evaluate the impact of salvage therapy with maribavir or letermovir on patient outcomes.

Off-Label Use of Letermovir as Preemptive Anti-Cytomegalovirus Therapy in a Pediatric Allogeneic Peripheral Blood Stem Cell Transplant

Despite the effectiveness of the currently available antiviral drugs in treating cytomegalovirus (CMV) infection, high rates of adverse effects are associated with their use. Moreover, a problem of increasing importance is the emergence of drug-resistant CMV infection. Here, we describe the first case of off-label use of letermovir (LMV) as preemptive antiviral therapy, in a pediatric allogeneic peripheral blood stem cell transplant recipient with ganciclovir-resistant CMV infection who was intolerant to foscarnet and unable to achieve viral clearance after seven doses of cidofovir. After the administration of LMV, a gradual reduction in viral load was observed and within 6 weeks of LMV treatment, after more than 6 months of positive CMV-DNAemia, the patient cleared the infection. No adverse effects associated with LMV were observed during treatment. In this pediatric study case, the off-label use of LMV for the treatment of CMV infection has been well tolerated and proved to be effective in leading to the suppression of viral replication.

Emergence of letermovir resistance in solid organ transplant recipients with ganciclovir resistant cytomegalovirus infection: A case series and review of the literature.

Ganciclovir (GCV)-resistant cytomegalovirus (CMV) infection is a common problem among solid organ transplant (SOT) recipients without prior CMV immunity (CMV D+/R-). GCV-resistant CMV represents a particular challenge for CMV management. Letermovir is a recently licensed antiviral agent for primary CMV prophylaxis in allogenic hematopoietic stem cell transplant (HSCT) recipients. Given the favorable safety profile and its oral bioavailability letermovir may be considered a valuable off-label option for secondary prophylaxis of GCV-resistant CMV in SOT recipients. Here, we describe our experience with letermovir as secondary prophylaxis for GCV-resistant CMV in two renal transplant recipients and review the literature in regard of previously published cases. Letermovir resistance emerged after a few months of secondary prophylaxis in the two renal transplant recipients. In both cases, the previously described UL56 C325Y letermovir resistance mutation was detected. In vitro studies of letermovir suggest a relatively low genetic barrier to resistance. Therefore, caution is warranted when using letermovir as secondary prophylaxis for GCV-resistant CMV infection.

Early Ganciclovir-Resistant Cytomegalovirus Infection in a Kidney Transplant Recipient: Could We Avoid It?

Early Ganciclovir-Resistant Cytomegalovirus Infection in a Kidney Transplant Recipient: Could We Avoid It?

Management of Antimicrobial Agents in Abdominal Organ Transplant Patients in Intensive Care Unit.

Purpose of ReviewEarly diagnosis of infections and immediate initiation of appropriate antimicrobials are crucial in the management of patients before and after organ transplantation. We reviewed the most recent literature and guidelines in this field and organized the current recommendations for healthcare professionals caring for critically ill organ transplant recipients.Recent FindingsThe incidence of multidrug-resistant organisms is increasing. Multidrug-resistant Gram-negative bacteria comprise about 14% of organisms. Vancomycin-resistant enterococci bloodstream infections are also on the rise, as 20.5% of nosocomial enterococci are now vancomycin-resistant, changing empiric antibiotic selection. Fluconazole-resistant Candida species comprise up to 46% of cases of candidemia in hospitalized patients. Consequently, new guidelines recommend primary use of echinocandins in patients with candidemia who have moderate-to-severe disease. Finally, the incidence of emergence of ganciclovir-resistant cytomegalovirus infection in patients is 5–12%, requiring early recognition and change to alternative regimens in the case of poor response to therapy.SummaryBloodstream infections are a major cause of mortality and morbidity in solid organ transplantation. Mortality as high as 24% and 50% have been reported with sepsis and septic shock respectively. As such, bloodstream infections should be diagnosed rapidly and intravenous antibiotics should be started immediately. Appropriate resuscitation should be initiated and the number and/or dose of immunosuppressive drugs should be reduced. Proper source control must also be achieved with radiologic drainage or surgical intervention as appropriate. Initial antibiotic treatment of these patients should cover both Gram-positive organisms, especially in the presence of intravascular catheters, and Gram-negative bacteria. Echinocandins like caspofungin should also be considered especially in critically ill patients, particularly if a patient has been on total parenteral nutrition or broad-spectrum antibiotics.

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

BackgroundDrug-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.MethodsThis 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.ResultsOf 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).ConclusionsUL97 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.

1747. Impact of Inappropriately Low Cytomegalovirus (CMV) Prophylaxis Dosing on CMV Outcomes Among Lung Transplant (LT) Recipients

BackgroundValganciclovir (VGCV) and ganciclovir (GCV) are commonly used to prevent CMV in at-risk lung transplant recipients (LTRs). Because renal function changes frequently in the post-transplant setting, antiviral under-dosing may occur. We sought to determine the frequency of GCV/VGCV under-dosing and its impact on CMV-related outcomes among LTRs.MethodsWe conducted a retrospective cohort study of all adult LTRs with a CMV seropositive donor (D+) between 2014 and 2016 at the Hospital of the University of Pennsylvania. Exposed patients were those with exposure to inappropriately low-dose GCV/VGCV. Unexposed patients were those whose antiviral dosing was consistently appropriate for their creatinine clearance. We employed a multivariable Cox proportional hazard analysis to determine the impact of low-dose prophylaxis on time to CMV infection post-transplant; prophylaxis dosing was incorporated as a time-varying covariate in this survival analysis.Results108 adults underwent CMV D+ LT during the study period. 46 (43%) experienced low prophylaxis dosing at some point during their prophylaxis course. 47 (43%) LTRs developed CMV viremia, of which 10 (9%) were still on prophylaxis. 20 (19%) LTRs developed CMV disease and 6 (6%) had ganciclovir-resistant CMV. In the multivariable Cox analysis, we found that there was not a significant association between exposure to any low-dose prophylaxis and the hazard of CMV infection (HR = 1.001, 95% CI 0.99–1.01, P = 0.75; Table 1), even among CMV seronegative recipients (D+/R−) (HR = 1.002, 95% CI 0.99–1.01, P = 0.68). When only those who received > 28 days of low-dose prophylaxis (N = 6, 6%) were evaluated, there was a trend toward an increased hazard of CMV infection (HR = 1.001, 95% CI 0.999–1.004, P = 0.18; Table 2).ConclusionCMV D+ LTR are frequently exposed to inappropriately low CMV prophylaxis dosing. This does not appear to significantly increase the risk for CMV infection, though prolonged subtherapeutic exposure merits further exploration as a risk factor for CMV outcomes in higher-risk patients. Disclosures All authors: No reported disclosures.

Persistent primary cytomegalovirus infection in a kidney transplant recipient: Multi-drug resistant and compartmentalized infection leading to graft loss

Cytomegalovirus (CMV) is one of the most common opportunistic infections after transplantation. To prevent CMV infections, universal prophylaxis and pre-emptive therapy with ganciclovir or its prodrug valganciclovir is applied. However, prolonged antiviral therapy may result in drug-resistance emergence. We describe a case of a 43-year-old CMV-seronegative patient who underwent kidney transplantation from a CMV-seropositive donor and developed CMV disease despite valganciclovir prophylaxis. CMV viral load increased even though valgangiclovir dose was augmented and immunosuppressive therapy reduced. CMV genotyping revealed mutations in the viral UL97 protein kinase, explaining ganciclovir-resistant CMV infection. The viral load failed to respond to foscavir, cidofovir and CMV-neutralizing immunoglobulins. Kidney allograft dysfunction developed 3 months post-transplantation with a histopathologic diagnosis of CMV nephropathy and potentially concomitant T-cell mediated rejection. A transplantectomy was performed on day 164 post-transplantation since the patient had uncontrollable CMV disease associated with a circulating multidrug-resistant DNA polymerase-mutant virus. Detailed monitoring in this patient demonstrated hallmarks of complicated CMV disease: (i) relatively rapid evolution of drug-resistant CMV mutants in the setting of persistent high blood viral loads, (ii) emergence of viral drug-resistance linked to acute graft rejection, (iii) transient and, thereafter, lack of response to various anti-CMV treatments, (iv) compartmentalization and heterogeneity of CMV viral populations, (v) possible differential ability of viral mutants to cause disease in the graft, and (vi) detection of minor viral variants by next generation sequencing. Translational research platforms that provide rapid molecular genotyping for detection of CMV drug-resistance are essential in guiding CMV disease management in high-risk transplant recipients.

Letermovir for the prevention of cytomegalovirus infection and disease in transplant recipients: an evidence-based review.

Cytomegalovirus (CMV) is a leading opportunistic infection in immune compromised patients, including allogeneic hematopoietic stem cell (HSCT) or solid organ transplant (SOT) recipients, where primary infection or reactivation is associated with increased morbidity and mortality. Antiviral drugs are the mainstay for the prevention of CMV infection and disease, most commonly with valganciclovir. However, valganciclovir use is often associated with adverse drug reactions, most notably leukopenia and neutropenia, and its widespread use has led to emergence of antiviral resistance. Foscarnet and cidofovir, however, are associated with nephrotoxicity. Letermovir, a novel CMV viral terminase inhibitor drug, was recently approved for CMV prophylaxis in allogeneic HSCT recipients. It has a favorable pharmacokinetic and tolerability profile. The aim of this paper is to review the evidence supporting the use of letermovir in allogeneic HSCT recipients, and how the drug impacts our contemporary clinical practice. In addition, we discuss the ongoing clinical trial of letermovir for the prevention of CMV in SOT recipients. The use of letermovir for treatment of CMV infection and disease is not yet approved. However, because of a unique mechanism of activity, we provide our perspective on the potential role of letermovir in the treatment of ganciclovir-resistant CMV infection and disease. Furthermore, drug-resistant CMV has emerged during use of letermovir for prophylaxis and treatment. Caution is advised on its use in order to preserve its therapeutic lifespan.

Cytomegalovirus viremia in lung transplantation during and after prophylaxis.

Lung transplantation has a high risk of cytomegalovirus (CMV) viremia and disease. Valganciclovir was planned for 6months in CMV recipient seropositive (R+) lung transplants (LTs) and given long-term in D+R- LTs. CMV viremia was monitored regularly during and after prophylaxis in all patients. Of 137 LTs, 22 were D+R-, 49 D+R+, 43 D-R+, and 23 D-R-, with median follow up 4.1years (IQR 2.1-6.2years). CMV viremia at any time occurred in 44.5% of LTs. CMV viral load >103 c/mL was uncommon (9/77 episodes). CMV viremia occurred at median 665days (IQR 271-1411days), in 5.1% LTs <6months, 20.3% LTs 6-12months, and 35.8% LTs >12months. CMV disease occurred in 6 (4.4%) LTs at an overall rate of 1.0 episode per 100 person-years: two of these cases were organ-specific disease, four were CMV syndrome. One case of ganciclovir-resistant CMV was diagnosed. D+R+ and D+R- LTs had higher viremia rates than the D-R+ group. No viremia occurred in D-R- LTs. CMV viremia was not associated with age, gender, type of LT, indication for LT, acute rejection, bronchiolitis obliterans syndrome, or mortality. Prophylaxis for 6months in D+R+ and D-R+, and past 12months in D+R- LTs, with long-term monitoring in all patients using a sensitive assay, and reinstitution of valganciclovir for low-level viremia was effective at markedly reducing the incidence of CMV disease. CMV D-R- LTs do not need routine CMV monitoring.

Use of Letermovir as Salvage Therapy for Drug-Resistant Cytomegalovirus Retinitis.

Treatment options for drug-resistant cytomegalovirus (CMV) are limited. Letermovir is a novel antiviral recently approved for CMV prophylaxis following hematopoietic cell transplantation, but its efficacy in other settings is unknown. We recently used letermovir for salvage treatment in four solid organ transplant recipients with ganciclovir-resistant CMV retinitis. All patients improved clinically without known adverse drug events. However, three patients failed to maintain virologic suppression, including two patients who developed genotypically confirmed resistance to letermovir while on therapy.