A Case Report of Successful Use of Twice-Daily Letermovir in the Treatment of Resistant Cytomegalovirus in a Small Bowel Transplant Recipient

Cytomegalovirus (CMV) is considered one of the most notable pathogens that affect patients after solid organ transplantation (SOT), especially small bowel transplant patients with a risk of high mortality rate. Its management relies historically on the use of CMV DNA polymerase inhibitors (namely, ganciclovir and valganciclovir). Second-line options include foscarnet and cidofovir, which are highly nephrotoxic and thus less preferred and only used in ganciclovir intolerance or resistance cases. Letermovir is a novel antiviral agent approved for CMV prophylaxis in hematopoietic stem cell transplant, but not for SOT (neither for prophylaxis nor for treatment).We report the first case on the successful use of letermovir in treating CMV disease in a small bowel transplant patient who failed to achieve viral clearance due to ganciclovir resistance and severe intolerance to foscarnet.     

Preemptive treatment of Cytomegalovirus infection in kidney transplant recipients with letermovir: results of a Phase 2a study

Cytomegalovirus (CMV) infection remains a significant cause of morbidity and mortality in transplant recipients. Letermovir (AIC246), is a novel anti‐HCMV drug in development, acting via a novel mechanism of action. In this proof‐of‐concept trial with first administration of letermovir to patients, 27 transplant recipients with active CMV replication were randomly assigned to a 14‐day oral treatment regimen of either letermovir 40 mg twice a day, letermovir 80 mg once a day, or local standard of care (SOC) in a multicenter, open‐label trial. Efficacy, safety, and limited pharmacokinetic parameters were assessed. All groups had a statistically significant decrease in CMV‐DNA copy number from baseline (40 mg BID: P = 0.031; 80 mg QD: P = 0.018; SOC: P = 0.001), and comparison of viral load reduction between treatment groups showed no statistically significant differences. Viral clearance was achieved for 6 of 12 patients (50%) in the letermovir groups versus two of seven SOC patients (28.6%). Letermovir treatment was generally well tolerated, no patient developed CMV disease during the trial. Both letermovir treatment regimens resulted in equally high trough level plasma concentrations. The efficacy, safety, and pharmacokinetics observed in these viremic transplant recipients indicate that letermovir is a promising new anti‐CMV drug.     

Letermovir in lung transplant recipients with cytomegalovirus infection: A retrospective observational study

Letermovir is a new antiviral drug approved for the prophylaxis of CMV infection in allogeneic stem cell transplants. The aim of the study was to assess the therapeutic efficacy of letermovir in difficult to treat CMV infections in lung transplant recipients. All lung transplant recipients between March 2018 and August 2020, who have been treated with letermovir for ganciclovir-resistant or refractory CMV infection were included in the study and analysed retrospectively. In total, 28 patients were identified. CMV disease was present in 15 patients (53.6%). In 23 patients (82.1%), rapid response was noticed, and CMV-viral load could be significantly decreased (>1 log₁₀) after a median of 17 [14–27] days and cleared subsequently in all of these patients. Five patients (17.9%) were classified as non-responder. Thereof, development of a mutation of the CMV UL56 terminase (UL-56-Gen: C325Y) conferring letermovir resistance could be observed in three patients (60%). Common side effects were mild and mostly of gastrointestinal nature. Mild adjustments of the immunosuppressive drugs were mandatory upon treatment initiation with letermovir. In addition to other interventions, letermovir was effective in difficult to treat CMV infections in lung transplant recipients. However, in patients with treatment failure mutation conferring letermovir, resistance should be taken into account.     

Cytomegalovirus infection in lung transplantation; current status, detection, prophylactic treatment

The control of the postoperative infectious disease is one of the important elements in transplantation. Among them, the control of the cytomegalovirus (CMV) infection may be said the most important in the management of the transplant recipient who is under the immunosuppression. This time, we review the status of the pre-transplant CMV infection in the donors and recipients of both brain-death and living-related lung transplantation that we performed, and report our prophylactic treatment for CMV infection and its results. The CMV positive rate of the recipients and donors of the lung transplantation that we experienced in Okayama University was 87%. We experienced 4 cases that developed CMV infection after lung transplantation. However, there is no case that died of a CMV-related infectious disease after lung transplantation to date. By the CMV mismatch transplant, it seemed that the frequency of the postoperative CMV disease was high in comparison with the transplant of recipient CMV (+). But, the control of the CMV infection after lung transplantation is thought to be possible if we give a proper prophylactic treatment even in CMV mismatch transplantation.     

First Report of Successful Treatment of Multidrug‐Resistant Cytomegalovirus Disease with the Novel Anti‐CMV Compound AIC246

We report the first case of cytomegalovirus (CMV) disease treated with AIC246, a novel anti‐CMV compound which targets the viral terminase complex and remains active against virus resistant to DNA polymerase inhibitors. A lung transplant recipient developed refractory multidrug‐resistant CMV disease involving the lungs, gastrointestinal tract and retina. His disease progressed despite treatment with all DNA polymerase inhibitors; multiple agents reported to have activity against CMV in case series, and reduction in his immunosuppressive medications. AIC246 which is in clinical development was obtained for emergency use, and combined with additional reduction in immunosuppression resulted in rapid clinical, virological and radiological resolution of disease. The patient has remained free of CMV disease or viremia off treatment for greater than 3 months. In summary AIC246, while still in development, may be a promising alternative to current therapies.     

Outcomes of patients with detectable CMV DNA at randomization in the phase III trial of letermovir for the prevention of CMV infection in allogeneic hematopoietic cell transplantation

Letermovir, a cytomegalovirus (CMV) terminase‐complex inhibitor, is indicated for prophylaxis of CMV infection and disease in adult CMV‐seropositive recipients of allogeneic hematopoietic cell transplantation (HCT). In a phase III, double‐blind, randomized trial, letermovir significantly reduced the risk of clinically significant CMV infection (CS‐CMVi) vs placebo through Week 24 post‐HCT. This analysis investigated outcomes in participants with detectable CMV DNA at randomization, who were excluded from the primary efficacy analysis. In total, 70 of 565 randomized participants had detectable CMV DNA at randomization (letermovir 48; placebo 22). Study treatment completion rates were greater in letermovir‐treated participants compared with placebo (52.1% vs 9.1%). The incidence of CS‐CMVi or imputed primary endpoint events through Week 24 were 64.6% and 90.9% in the letermovir and placebo groups, respectively (treatment difference ?26.1%; P = .010). Kaplan‐Meier event rates for CS‐CMVi onset through Week 14 (end‐of‐treatment period) were 33.1% for letermovir and 86.6% for placebo (P < .001). Median viral loads at the CS‐CMVi events was similar in both treatment arms. All‐cause mortality through Week 24 posttransplant was 15.0% for letermovir and 18.2% for placebo; through Week 48, mortality rates were 26.5% and 40.9%, respectively (P = .268). Overall, clinical outcomes were similar to those reported for participants with undetectable CMV DNA at randomization.     

Cytomegalovirus and Lung Transplantation

Cytomegalovirus (CMV) infection remains a serious problem in lung transplant recipients. Development of potent oral antiviral agents, molecular techniques for the detection of infection and its response to therapy and the emergence of isolates with antiviral resistance have had significant impacts on the approach to CMV in these patients. This article discusses the following issues as part of a comprehensive CMV management strategy in lung transplant recipients: (1) Prevention strategies in the era of potent oral antiviral agents, (2) the role of new diagnostic techniques in the management of CMV, (3) treatment regimens for established CMV infection or disease, (4) the potential impact of treatment of CMV on the indirect effects on long-term allograft function, and (5) the incidence, risk factors for and impact of ganciclovir resistance following lung transplantation.     

Incidence,Risk Factors,and Outcomes of Delayed-Onset Cytomegalovirus Disease in a Large,Retrospective Cohort of Heart Transplant Recipients

BackgroundDelayed-onset cytomegalovirus (CMV) disease can occur among heart transplant recipients after stopping anti-CMV prophylaxis. We evaluated a large, retrospective cohort of heart transplant recipients in the United States through the use of billing data from 3 Healthcare Cost and Utilization Project (HCUP) State Inpatient Databases (SID) to determine the epidemiology of delayed-onset CMV disease coded during hospital readmission.MethodsWe identified 2280 adult heart transplant recipients from 2004 to 2010 through the use of the California, Florida, and New York SID. Demographics, comorbidities, heart failure etiology, CMV disease, and inpatient death were identified. CMV disease was classified as early-onset (≤100 days) or delayed-onset (>100 days after transplant). Possible tissue invasion by CMV was determined through the use of codes for CMV pneumonitis, hepatitis, and gastrointestinal endoscopy. Multivariate analysis was performed with the use of Cox proportional hazards models.ResultsDelayed-onset CMV disease occurred in 7.5% (170/2280) and early-onset CMV disease occurred in 2.0% (45/2280) of heart transplant recipients. Risk factors for delayed-onset CMV disease included residence in a non-metropolitan locale (aHR. 1.8; 95% confidence interval [CI], 1.0–3.3) and ischemic cardiomyopathy as heart failure etiology (aHR, 1.8; 95% CI, 1.3–2.5). Inpatient death >100 days after transplant was associated with delayed-onset CMV disease with possible tissue invasion (aHR, 2.0; 95% CI, 1.1–3.8), transplant failure or rejection (aHR, 4.0; 95% CI, 2.7–5.8), and renal failure (aHR, 1.5; 95% CI, 1.1–2.0).ConclusionsDelayed-onset CMV disease is more common than early-onset CMV disease among heart transplant recipients. These results suggest that delayed-onset tissue-invasive CMV disease may be associated with an increased risk of death.     

Acute Cytomegalovirus Cholecystitis Following Renal Transplantation

Solid organ transplant recipients are at risk of infection from cytomegalovirus (CMV). A wide range of disease is associated with CMV infection and we report two cases of CMV cholecystitis in patients following renal transplantation. Both patients presented with severe hemorrhagic cholecystitis, which required immediate resuscitation and emergency cholecystectomy. The diagnosis of CMV infection was confirmed in both cases using CMV-specific staining of the gallbladder. The diagnosis of CMV cholecystitis must be considered in all patients with upper abdominal pain after renal transplantation.     

Preemptive Strategy for Ganciclovir Administration Against Cytomegalovirus in Liver Transplantation Recipients

In utilizing a preemptive strategy to minimize the occurrence of symptomatic cytomegalovirus (CMV) infection following liver transplant, only patients with proven CMV activity by direct detection are treated. We applied the following preemptive strategy for CMV infection to 49 sequential liver transplant recipients between 1998 and 2001. Patients were monitored for CMV activity using CMV p65 antigen assay for the first 10 months of the study. Thereafter, we changed the detection method to a quantitative PCR for plasma CMV-DNA. All patients were monitored post transplant, weekly for the first 3 months and then monthly. Only patients with detected CMV activity were treated with ganciclovir. Patients were divided into four groups, based on donor (D) and recipient (R) CMV status. In seven out of 49 patients (14.3%) CMV activity was detected: four in group D+/R-, and three in group D-/R-. Five out of these seven patients had asymptomatic CMV infection. Symptomatic CMV infection developed only in two of these seven patients, to give total rate of 4.1% (2/49). All seven patients developed CMV IgG antibody. 'Transient' CMV replication detected by PCR in five patients in group D+/R+ was not defined as infection. No patients developed organ-invasive CMV disease. The cost of anti-CMV treatment using the preemptive strategy was $1000/patient/1st year. Using preemptive strategy, early detection of CMV infection was achieved, allowing timely treatment. The use of ganciclovir for CMV infection in only 4.3% of the patients should have a positive impact on minimizing the risk of ganciclovir-resistant virus, and should reduce the cost of CMV prevention strategies.     

Cytomegalovirus infection in seronegative patients treated with prophylaxis: case-controlled study

Primary cytomegalovirus (CMV) infection is common in infancy with approximately 90% to 95% of subjects developing antibodies against this virus. CMV seronegative renal allograft recipients generally receive this infection with a graft or with blood transfusions, showing a high morbidity and mortality. Prophylaxis in these patients has shown good results; however, the published studies have included a small number of patients. Our case-controlled study evaluated 163 kidney transplant recipients: 76 seronegatives for CMV and 87 seropositive for CMV as controls. The evaluated parameters were: CMV infection, CMV disease, renal function, and survival of the patient and graft. We studied our experience among CMV seronegative patients treated with various prophylaxis guidelines. Our conclusions were that CMV prophylaxis in seronegative patients was effective because it showed a risk of infection that was equal (or even less) than that in seropositive patients and revealed a delay in the onset of the disease. CMV seronegativity may be a positive prognostic factor for graft survival.     

Cytomegalovirus infection may cause ureteral necrosis

Cytomegalovirus (CMV) infection has protean presentation among immunocompromised patients, but the urinary tract is rarely involved. We report a case of extensive ureteral necrosis in a renal transplant, 12-year-old patient with typical histological feature of CMV inclusions. The role of CMV was confirmed by immunohistochemical analysis and concomitant CMV DNA detection in peripheral blood leukocytes by polymerase chain reaction analysis. CMV infection can, therefore, be regarded as a possible cause of ureteral necrosis in renal transplant recipients.     

Cytomegalovirus ischemic colitis of a diabetic renal transplant recipient

We report a diabetic renal transplant recipient with cytomegalovirus (CMV) disease who presented with tarry stool diarrhea because of multiple colonic ulcerations. Histopathology revealed diffuse colonic ulcers following a process of ischemic vasculitis. The colonic ulcers disappeared dramatically after 2 wk of intravenous ganciclovir therapy. Hyper-immunosuppression was initially suspected but acute rejection (AR) developed after immunosuppressive reduction during the ganciclovir therapy. The AR was successfully reversed and the dosage of cyclosporine was returned to the same level prior to the onset of CMV disease. Our experience suggests that ganciclovir is quite effective for healing colonic ulcers caused by CMV and acute allograft rejection may occur during therapy.     

Cytomegalovirus in renal transplantation

Cytomegalovirus (CMV) was first isolated from the salivary gland and kidney of two dying infants with cytomegalic inclusion bodies and reported in 1956 (1). Two other laboratories isolated CMV at approximately the same time. Thus, CMV was initially called "salivary gland virus" or "salivary gland inclusion disease virus". In 1960, Weller et al. (2) proposed the use of the term cytomegalovirus. Klemola and Kaarianinen (3) first described CMV mononucleosis, the principal presentation of previously healthy individuals, in 1965. CMV was first isolated in a renal transplant patient in 1965,     

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

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.     

The Risk Factors for Cytomegalovirus Syndrome and Tissue-invasive Cytomegalovirus Disease in Liver Transplant Recipients Who Have Cytomegalovirus Antigenemia

Cytomegalovirus (CMV) infection is not only a common complication after liver transplantation (OLT), but also a significant contributing factor to morbidity and mortality. We investigated risk factors for CMV syndrome and tissue-invasive CMV disease in CMV antigenemia patients after OLT in a CMV endemic area. CMV antigenemia was regarded to be >1 positive CMV pp65 antigen positive cell per 400,000 white blood cells. We examined the epidemiology, clinical characteristics, and laboratory findings of liver transplant patients with CMV syndrome and tissue-invasive CMV disease. The incidence of CMV syndrome among patients with CMV antigenemia was 10.5% (37/353) and that of tissue-invasive CMV disease, 3.1% (11/353). Upon multivariate analysis the risk factors for CMV syndrome and tissue-invasive CMV disease were infection, low albumin level, high total bilirubin content, and high CMV peak titer. The 1-y, 2-y, and 3-year survival rates of subjects without CMV syndrome were 96.2%, 85.4% and 82.2% versus without tissue-invasive CMV disease, 86.9%, 83.0%, and 80.1%, or 70.3%, 56.1% and 51.8% for CMV syndrome or 72.7%, 62.3%, 49.9% for tissue-invasive CMV disease. The survival curve of patients without were superior to those with CMV syndrome (P = .000). Because OLT recipients had risk factors such as infection, low albumin level, high total bilirubin content, and high CMV peak titer, they were carefully monitored and aggressively managed due to the poor survivals of patients with CMV syndrome.     

Cytomegalovirus Disease in Renal Transplant Recipients: A Single-Center Experience

Cytomegalovirus (CMV) disease is an important complication and an independent risk factor for acute rejection and recipient morbidity-mortality. The aim of this study was to review the results of CMV disease in renal transplant recipients. Method. We have retrospectively analyzed CMV disease in 120 renal transplant recipients and recorded the demographic features, clinical manifestations, and immunosuppressive regimens. Results. Twenty-nine recipients (24.1%) developed CMV disease after a median interval of 2.8 ± 2,6 months from transplantation. CMV disease developed in 36.3% of recipients who received basiliximab as induction therapy and 21.4% of recipients who were treated with anti-thymocyte globulin (ATG). The most commonly used immunosuppressive regimen was cyclosporine-A (CsA)-based (79.3%). The mean cumulative steroid dose until the diagnosis was 3,600 mg methyl prednisolone per patient. Malaise, fever, and diarrhea were the most common symptoms. Gastritis, pneumonia, and transaminitis were the most commonly seen end-organ involvements. Frequent laboratory findings were leukopenia (34.5%), increased serum creatinine level (34.5%), and leukocytosis (20.7%). We performed renal biopsy to seven patients and detected acute rejection in four patients. In 25 patients, immunosuppressive treatment was modified. Relapsing CMV disease was seen in seven patients. Conclusion. In our study, CMV disease was seen in recipients who were treated with basiliximab, a finding similar to recipients who were treated with ATG.     

Cytomegalovirus infection of the native ureter after liver-kidney transplantation

We report a case of invasive cytomegalovirus (CMV) infection in the native ureter of a patient 7 years after liver-kidney transplantation. Previous reports of CMV ureteritis in transplant patients have involved only the allograft ureter, usually within 3 months of transplantation. The common characteristics of these patients, the possible risk factors, and the diagnostic findings of CMV ureteritis are discussed. Combined surgical and medical intervention are required for successful treatment.     

Impact of Cytomegalovirus Disease in D+/R– Kidney Transplant Patients Receiving 6 Months Low‐Dose Valganciclovir Prophylaxis

Late‐onset cytomegalovirus (CMV) disease remains common in CMV serology naïve kidney transplant patients of CMV serology positive organs (D+/R–) despite the use of antiviral prophylaxis. We studied clinical efficacy of 6‐month low‐dose valganciclovir (VGCV) prophylaxis, risk factors for late‐onset CMV disease and its impact on kidney transplant outcomes. Between October 2005 and December 2009, 166 consecutive D+/R– kidney alone and simultaneous pancreas and kidney transplant patients received VGCV 450 mg daily for 6 months after transplantation. After a median follow‐up of 3.2 years, 30 cases of CMV disease occurred within the first 2 years after transplantation with a cumulative incidence of 11.5 and 18.1% at 1 and 2 years, respectively. The use of an induction agent with rabbit antithymocyte globulin and older donor age were factors associated with the risk of late‐onset CMV disease (AHR 2.91, 95% CI 1.18–7.20, p = 0.021 and AHR 1.03, 95% CI 1.01–1.06, p = 0.016, respectively). Late‐onset CMV disease was associated with increased risk for death‐uncensored graft loss (AHR 2.95, 95% CI 1.15–7.61, p = 0.025). In conclusion, late‐onset CMV disease continues to negatively impact kidney transplant outcome despite 6‐month low‐dose VGCV prophylaxis. Investigations focusing on novel preventive approaches should be emphasized.