Higher Risk Of Cytomegalovirus Infection Research Articles

Real-life use of letermovir prophylaxis for cytomegalovirus in heart transplant recipients.

Cytomegalovirus (CMV) remains the predominant opportunistic infection following solid organ transplantation (SOT). While valganciclovir is the drug of choice for CMV prophylaxis, its utility can be compromised due to the risk of cytopenia. Letermovir, a novel agent approved for CMV prophylaxis in allogeneic hematopoietic stem cell transplant recipients and high-risk kidney transplant recipients, exhibits reduced toxicity. This study aims to present the practical application of letermovir as both primary and secondary prophylaxis against CMV in heart transplant recipients (HTR). In this observational, retrospective, single-center study, we included all consecutive adult HTRs from June 2020 to January 2022 who were administered letermovir for CMV prophylaxis. We documented instances of CMV breakthrough infections, side effects related to letermovir, changes in neutropenia following the switch from valganciclovir to letermovir, and any drug interactions with the immunosuppressive regimen. The study comprised 10 patients: two received primary prophylaxis with letermovir due to a high risk of CMV infection (donor-positive, recipient-negative serostatus), and eight received it as secondary prophylaxis following a CMV infection. The median duration of letermovir administration was 8 months (range 3-12 months). No CMV breakthrough infections were reported while on prophylaxis. However, three patients experienced CMV breakthrough infections after discontinuing letermovir prophylaxis (30%). No significant side effects were observed, although one patient reported digestive intolerance. Among the nine patients on tacrolimus, six needed reduced doses after switching to letermovir. This real-life study appears to support the effectiveness of letermovir prophylaxis in HTR. Nonetheless, the risk of CMV infection post-treatment cessation is notable. Further drug monitoring and research on the efficacy of letermovir for CMV prophylaxis in SOT patients is warranted.

Body Surface Area Valganciclovir Prophylactic Dosing is Associated with a Higher Rate of Drug-Associated Toxicities Compared to Body Weight Dosing in Pediatric Solid Organ Transplant Recipients

Abstract Background Valganciclovir (VGCV) is used for prevention of cytomegalovirus (CMV) in pediatric solid organ transplant (SOT) recipients who are at moderate or high risk for CMV infection or reactivation. Optimal dosing is not well defined, and both weight-based (WB) (15 mg/kg/dose) and body surface area-based (BSA) dosing (7 x BSA x creatinine clearance with an upper limit of 150 mL/min/1.73 m2) are used. We used a recently completed retrospective study on VGCV toxicity to compare the effects of these 2 dosing strategies on the proportion and the odds of CMV DNAemia, neutropenia, lymphopenia, and toxicity-related VGCV discontinuation or dose modification. Methods Data was collected from 6 US centers. Inclusion criteria were SOT recipients <20 years of age transplanted between January 2016 and December 2019, anticipated to receive VGCV prophylaxis with either dosing method for >/=3 months, and availability of >/=6 months of follow-up data post-transplant. Neutropenia and lymphopenia were defined as absolute neutrophil or lymphocyte count <1000 cells/microL. The number of patients who had premature discontinuation or dosing modification attributed to leukopenia or acute kidney injury (AKI) was quantified. Anticipated VGCV duration, dosing strategy, and threshold for making VGCV changes were at the discretion of each center for each patient. Cytopenias or toxicities that occurred within 15 days of SOT were excluded. Data were collected for one-year post-transplant and analyzed using Stata version 17.0. Groups were compared using Mann Whitney U test for continuous variables and chi-square test for categorical variables; logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (CI) with multivariable analysis. Results 412 patients met inclusion criteria. 312 patients were treated with WB and 100 with BSA dosing. Median age at transplantation was 5.1 (IQR 1.8-11.8) years and 42.7% were female. Transplanted organs included: liver 35.4%, kidney 33.5%, heart 22.3%, lung 6.6%, and other 2.2%. Within one year of transplantation, 23.4% and 12.2% of the WB group and 31.0% and 16% of the BSA group had at least one episode of CMV DNA detection in the plasma (DNAemia) and breakthrough CMV DNAemia while on VGCV prophylaxis, respectively (p=0.1 and p=0.3). There was no statistically significant difference in the odds of CMV DNAemia or breakthrough CMV DNAemia between dosing groups at one year when adjusted for: transplanted organ, CMV risk based on pre-transplant serostatus, duration of anticipated prophylaxis, age, receipt of CMV immunoglobulin, anti-thymocyte globulin, basiliximab, alemtuzumab, mycophenolate and corticosteroid (aOR=1.1, 95% CI: 0.6-1.8, p=0.8 and aOR=1.4, 95% CI: 0.6-2.9, p=0.4). However, the risk of all drug toxicity while on prophylaxis were significantly greater in BSA compared to WB group: neutropenia (50.0% vs 29.3%), lymphopenia (51.0% vs 15.0%), and toxicity-related VGCV discontinuation or modification (21% vs 6.7%) (each p<0.001). The BSA group had higher odds of neutropenia (aOR=2.3, 95% CI: 1.4-3.7, p=0.001), lymphopenia (aOR=7.0, 95% CI: 3.9-12.4, p<0.001), and toxicity-related VGCV discontinuation or modification (aOR=4.6, 95% CI: 2.2-9.3, p<0.001) while on prophylaxis when adjusted for age, organ, anticipated VGCV duration, and receipt of trimethoprim-sulfamethoxazole, anti-thymocyte globulin, basiliximab, alemtuzumab, mycophenolate and corticosteroid. Conclusions Results of this study indicate that BSA dosing of VGCV is associated with a significantly greater risk of toxicity without a decrease in CMV DNAemia.

New Perspectives in Cytomegalovirus After Transplant: The Role of Immunosuppressant Management.

New Perspectives in Cytomegalovirus After Transplant: The Role of Immunosuppressant Management.

Effective CMV prophylaxis with high-dose valaciclovir in allogeneic hematopoietic stem-cell recipients at a high risk of CMV infection.

Cytomegalovirus (CMV) infection increases mortality and morbidity following allogeneic hematopoietic stem-cell transplantation (alloHSCT). Universal antiviral prophylaxis with letermovir is effective but unsubsidized in Australia. Valaciclovir demonstrates anti-CMV activity in high doses, but few current real-world studies explore its use as primary prophylaxis in high-risk patients post-alloHSCT. We performed a retrospective analysis of alloHSCT recipients at high risk of clinically significant CMV infection (cs-CMVi), defined as a plasma CMV DNA viral load of >400IU/ml requiring preemptive therapy, or CMV disease. High-risk recipients were CMV seropositive and underwent T-cell depleted, haploidentical or umbilical cord stem-cell transplants. Consecutive patients transplanted from July 2018 to January 2020, treated with valaciclovir 2g TDS from day +7 to +100 (HD-VALA), were compared to a historical cohort (July 2017-June 2018) who only received preemptive CMV therapy, and standard valaciclovir (SD-VALA) for varicella/herpes prophylaxis. We compared incidence of and time to cs-CMVi. In the SD-VALA cohort (n=27, median CMV follow-up duration 259 days), 23/27 (85%) developed cs-CMVi at a median of 39 days. For the HD-VALA cohort (n=35, median CMV follow-up duration 216 days), 19/35 (54%) developed cs-CMVi, at a median of 68 days. Time to cs-CMVi was significantly longer in HD-VALA cohort (p<.0001). On multivariate analysis, HD VALA reduced the risk of cs-CMVi (HR 0.32, p=.0005). In alloHSCT recipients at high risk for cs-CMVi, HD-VALA resulted in lower cumulative reactivation, and delayed reactivation, reducing requirement for preemptive CMV therapy in the early post-engraftment period.

Seroprevalence of Cytomegalovirus in Haemodialysis Patients

Cytomegalovirus (CMV) is prevalent worldwide. It belongs to the β-herpesvirinae subfamily of Herpesviridae and comprises a double-stranded linear DNA genome and capsid, surrounded by an envelope. CMV infection is most prominently found in patients with kidney failure caused by various possible reasons such as urinary tract infection or systemic disease and are undergoing dialysis. The present study was conducted during the period of March 2020 to April 2021. It included 96 patients with chronic kidney disease undergoing hemodialysis (44 of patients were women and 52 men) within the age range of 11-70 years. Five-mL of the venous blood sample was drawn from each patient to conduct the rapid antibody test for the presence of CMV-specific antibodies (both IgG, and IgM). This study showed that the seroprevalence of CMV infection among haemodialysis patients was 75%. The seropositivity for CMV-IgG was 72.9% which was significantly higher than that for CMV-IgM (2.1%) for both sexes. The present study further demonstrated that the prevalence of positive CMV-IgG in males was higher than that in females (38.5% and 34.4%, respectively). In addition, the positivity of CMV-IgM was highest in the age group 61–70 years old (2.1%), while the positivity of CMV-IgG was highest in patients age groups 41–50 years (24%). The present study revealed a high seroprevalence of CMV infection among haemodialysis patients in Basrah City. The elevated seroprevalence could be related to many factors, including the endemicity of the virus, public health, patient immunity, environmental factors, and geographical location. CMV infection increases with age, and the infection rate in men was higher than that in women. The seroprevalence rate of CMV-IgG antibodies was higher than that of CMV-IgM antibodies, indicating a previous infection or reactivation of CMV virus among haemodialysis patients, leading to a high risk of CMV infection.

Effectiveness of Prophylactic Human Cytomegalovirus Hyperimmunoglobulin in Preventing Cytomegalovirus Infection following Transplantation: A Systematic Review and Meta-Analysis.

Cytomegalovirus (CMV) is a common infection occurring in patients undergoing solid organ transplantation (SOT) or hematopoietic stem cell transplantation (HSCT). CMV-specific hyperimmunoglobulin (CMVIG) has been used for the past four decades and is typically administered either prophylactically or pre-emptively. The present meta-analysis evaluated CMV infection rates in SOT patients who received prophylactic CMVIG. PubMed and the Cochrane Library were searched for studies published up to October 2021. The primary endpoint was CMV infection rate. Thirty-two SOT studies were identified (n = 1521 CMVIG-treated and n = 1196 controls). Prophylactic CMVIG treatment was often associated with a lower risk of CMV infection in transplant recipients. The average CMV infection rate was 35.8% (95% confidence interval [CI]: 33.4–38.2%) in patients treated prophylactically with CMVIG and 41.4% (95% CI: 38.6–44.2%) in the control group not receiving CMVIG (p = 0.003). Similar results were observed in analyses limited to publications evaluating currently available CMVIG products (Cytotect CP and Cytogam; p < 0.001). In combination with the established safety profile for CMVIG, these results suggest that prophylactic CMVIG treatment in patients undergoing solid organ transplantation may be beneficial, particularly in those at high risk of CMV infection or disease.

Epidemiology of cytomegalovirus infection in pregnancy in Israel: Real-world data from a large healthcare organization.

Congenital cytomegalovirus infection (cCMVi) is the leading cause of nonhereditary sensorineural hearing loss among newborns. Women newly acquiring cytomegalovirus infection (CMVi) during pregnancy have the highest risk of vertical transmission. This study aimed to describe the epidemiology of CMVi in pregnancy in a large healthcare database. A retrospective cohort study was performed using the Maccabi Healthcare Services database (Israel). Women aged 18-44 years old on July 1, 2013 with no record of pregnancy in the prior 6 months were followed through December 31, 2017 for first pregnancy occurrence. Pregnancy outcomes (live birth, spontaneous/therapeutic abortions, stillbirth, and uncertain outcomes) were captured. CMV test results were obtained to assess serostatus at the start of pregnancy (SoP) and primary CMV infection (CMVi) during pregnancy. Associations of demographic and reproductive factors with pCMVi were investigated (multivariable logistic regression). The study included 84 699 pregnant women (median age = 31 years; interquartile range = 28-35). Live birth, fetal loss, and uncertain pregnancy outcomes accounted for 76.8%, 18.2%, and 5.0%, respectively. The seroprevalence of CMV at the start of pregnancy in this cohort was 63.4% (95% confidence interval [CI]: 63.1-63.7). Among seronegative women with available test results (n = 10 657), CMVi incidence was 14.5 per 1000 (95% CI = 12.2-16.7). In multivariate logistic regression models adjusting for maternal age, CMVi was significantly associated with having one or more prior live births (odds ratio [OR]: 3.8 [95% CI: 2.6-5.4]) and having a child less than 6 years of age (OR: 4.3 [95%CI: 3.0-6.1]). One in three pregnant women in Israel is at risk for primary CMVi. This study demonstrates that real-world electronic healthcare data can be leveraged to support clinical management and development of interventions for congenital CMV by identifying women at high risk for CMVi during pregnancy.

The NFKB1 Promoter Polymorphism (-94ins/delATTG) Is Associated with Susceptibility to Cytomegalovirus Infection after Kidney Transplantation and Should Have Implications on CMV Prophylaxis Regimens.

Infections with cytomegalovirus (CMV) are one of the most frequent opportunistic infections in kidney transplant recipients. Current risk-adapted CMV chemoprophylaxis regimens are based almost solely on the donor and recipient CMV serostatus. Of note, the NFKB1 -94ins/delATTG promoter polymorphism was recently associated with a higher risk of CMV infection. Since single genetic association studies suffer from poor reliability for drawing therapeutic implications, we performed this confirmatory study and included 256 kidney transplant recipients from 2007 to 2014 in this retrospective study. Patients were genotyped for the -94ins/delATTG NFKB1 promoter polymorphism and followed up for 12 months. The incidence of CMV infection within 12 months after kidney transplantation was 37.5% (33/88) for the ins/ins, 21.5% (28/130) for the ins/del, and 23.7% (9/38) for the del/del genotypes (p = 0.023). Moreover, we evaluated the time of CMV infection onset. Ins/ins carriers had primarily late-onset CMV infection (median 194 days; interquartile range (IQR) 117–267 days) compared with heterozygous (ins/del; median 158 days; IQR 82–195 days) and homozygous deletion allele carriers (del/del; median 95 days; 84–123 days). Multivariate-restricted Cox regression model confirmed the ins/ins genotype to be an independent risk factor for the development of late-onset CMV infections. These findings should have an impact on post-kidney transplantation CMV chemoprophylaxis regimens.

1075. Absolute Lymphocyte Count as a Predictor of Cytomegalovirus (CMV) Infection and Recurrence in Hematopoietic Stem Cell Transplant (HSCT) Recipients

BackgroundCytomegalovirus (CMV) is a serious complication following Hematopoietic Stem Cell Transplant (HSCT) and can lead to serious organ disease and mortality. This study aimed to investigate the association between absolute lymphocyte count (ALC) and CMV to determine whether ALC could help to identify those at an increased risk of CMV infection and recurrenceMethodsAdults undergoing HSCT between 2011 and 2016 at Rigshospitalet, Denmark were included. Cox proportional hazards models investigated risk factors, including ALC, for CMV infection in the first year post-transplant and recurrent CMV infection 6 months after clearance and stopping CMV treatment for the first infection. For the primary outcome ALC was investigated as a time-updated risk factor lagged by 7 days, and for recurrent CMV, ALC measured at the time at the time of stopping treatment for the first CMV infection was investigated (+/- 7 days).ResultsOf the 352 HSCT recipients included, 57% were male, 40% received myeloablative conditioning, 42% had high risk (D-R+) CMV IgG serostatus at transplant and the median age was 56 (IQR 43-63). 143 (40.6%) patients had an episode of CMV DNAemia a median of 47 days after transplant (IQR 35-62). A lower current ALC (≤ 0.3 x109/L) was associated with a higher risk of CMV infection in univariate analysis compared to a high current ALC (> 1 x109/L). However, this association was attenuated after adjustment, particularly for acute graft versus host disease (Figure). 102 HSCT recipients were investigated for risk of recurrent CMV of which 41 (40.2%) had a recurrent CMV episode a median of 27 days (IQR 16-50) after stopping CMV treatment for the first infection. A lower ALC (≤ 0.3 x109/L) at the time of stopping CMV treatment was associated with a significantly higher risk of recurrent CMV after adjustment (Figure). A higher peak viral load (> 1500 IU/ml) during the first episode of CMV infection was also associated with an increased risk of recurrent CMV (aHR 2.47, 95%CI 1.00-6.10 compared to < 750 IU/ml).Association between absolute lymphocyte count (ALC) and risk of CMV infection and recurrent CMV within 6 months. **First CMV infection multivariable model also adjusted for sex, CMV serostatus, age, year of transplant, Charlson Comorbidity Index, Anti-thymocyte globulin (ATG) given, HLA donor-recipient matching, and acute graft versus host disease (time-updated) *Recurrent CMV infection multivariable model also adjusted for conditioning regimen, sex, CMV serostatus, age, year of transplant Anti-thymocyte globulin (ATG) given, HLA donor-recipient matching, and acute graft versus host disease and peak CMV viral load during the first CMV infectionConclusionA lower ALC at the time of stopping treatment for the first CMV infection was associated with an increased risk of recurrent CMV and could be used to help guide decisions for augmented CMV surveillance and clinical awareness of CMV disease symptoms in these patients. Disclosures All Authors: No reported disclosures

1079. The Risk of Cytomegalovirus (CMV) Infection and Recurrence Among Solid Organ Transplant Recipients

BackgroundSolid organ transplant (SOT) recipients are at a high risk of developing cytomegalovirus (CMV) post-transplant (tx) with many experiencing a recurrence shortly after clearing the first episode. We aimed to identify risk factors associated with CMV infection and recurrence.MethodsSOT recipients (≥ 18 years) transplanted between 2011-2016 were investigated for factors associated with CMV infection within 1 year from baseline and recurrent CMV within 6 months of stopping CMV treatment for the first infection using cumulative incidence curves and Cox proportional hazards models. Baseline was defined as either tx date or date of stopping CMV prophylaxis for those initiating CMV prophylaxis within 7 days of tx. Individuals with breakthrough CMV while on prophylaxis were excluded (n=29).Figure 1 Risk of CMV infection in 755 SOT recipients in the first year from baseline, stratified by CMV serostatus. Baseline was defined either the date of transplant (n=285) or stopping CMV prophylaxis (n=470). Figure 2 Factors associated with CMV infection in the first year from baseline. Baseline was defined either the date of transplant (n=285) or stopping CMV prophylaxis (n=470). ResultsWe included 755 SOT recipients, 173(23%) developed CMV infection within one year of baseline with CMV disease present at diagnosis in 17% of the cases. The risk of CMV infection was lower in patients with low (aHR 0.19, 95%CI 0.12-0.29) and intermediate (aHR 0.26, 95%CI 0.18-0.36) risk CMV IgG serostatus compared to high risk (Figure1). Liver and lung tx, female sex, older age and year of tx were also associated with an increased risk of CMV infection (Figure 2). Among the 470 (62%) patients who received CMV prophylaxis those who received < 85 days had a higher risk of CMV infection than those receiving ≥ 85 days (aHR 1.80, 95%CI 1.19-2.72).99 recipients were investigated for recurrent CMV; 40 (40%) experienced relapse within 6 months of stopping treatment for their first infection. The risk of recurrent CMV was significantly lower in those with low (aHR 0.20, 95%CI 0.06-0.74) and intermediate risk serostatus (aHR 0.40, 95%CI 0.19-0.84) (Figure 3). Older age (aHR 1.23 per 5 years older, 95%CI 1.06-1.44) was also significantly associated with recurrent CMV infection (Figure 4).Figure 3 Risk of recurrent CMV infection in the 6 months following clearance and stopping of treatment for the first CMV infection (N=99), stratified by CMV serostatus at the time of transplant Figure 4 Factors associated with recurrent CMV infection within 6 months of stopping treatment for the first CMV infection ConclusionRecurrent CMV infection remains a significant complication among SOT recipients, especially in those with high risk CMV IgG serostatus. These findings highlight the necessity to successfully treat and monitor this subgroup following their first infection. Novel medical interventions and strategies to prevent CMV infection are of particular importance to this high risk group.Disclosures All Authors: No reported disclosures

Kidney function of Japanese children undergoing kidney transplant with preemptive therapy for cytomegalovirus infection.

Cytomegalovirus (CMV) infection is one of the major factors that affect morbidity and mortality in kidney transplant (KTx) patients. The rate of CMV seropositivity in children before KTx is lower than that in adults; therefore, pediatric KTx patients have a higher risk of CMV infection. In Japanese pediatric KTx patients, preemptive therapy for CMV infection is a main conventional therapy. This study investigated whether this preemptive treatment would affect kidney function at 2years post-KTx. A total of 163 patients, that is approximately half of the Japanese pediatric KTx patients nationwide, were recruited to participate in our study. We compared the values of the sequential estimated glomerular filtration rate (eGFR) at two years post-KTx and other influencing factors in CMV viremia, CMV disease, and no-infection groups. Cytomegalovirus infection after KTx occurred in 75 patients (46.0%), 38.7% of whom developed CMV disease. The sequential eGFR values post-KTx did not differ significantly between the three groups. CMV infection was not significantly correlated with other factors, other infections (including Epstein-Barr [EB] virus infection), acute rejection (AR), or adverse events. Only prolonged duration of total hospitalization was significantly associated with CMV infection (P=.002). In the multivariate analysis, younger age, CMV infection, and adverse effects were independently significantly related to prolonged total hospitalization. Preemptive therapy for CMV infection evidenced by viremia and disease did not significantly influence kidney function in Japanese pediatric KTx patients at two years after the operation.

Phase 2 Study for Kidney Transplant Recipients at High-Risk of Cytomegalovirus Infection

Phase 2 Study for Kidney Transplant Recipients at High-Risk of Cytomegalovirus Infection

CYTOMEGALOVIRUS RETINITIS WITH BELATACEPT IMMUNOSUPPRESSION

To report two cases of cytomegalovirus (CMV) retinitis in renal transplant patients after conversion to belatacept immunosuppression. Case report. Case A was a 41-year-old African American man with no ocular history, chronic hepatitis B infection on entecavir, status-post living relative renal transplant for end-stage renal disease secondary to IgA nephropathy presented with a chief complaint of "blurry vision" in his right eye. Fundoscopic examination of the right eye revealed perivascular retinitis of the superior arcade extending temporally and a lesion nasal to the optic disk. The patient was diagnosed with CMV retinitis with macular involvement. Case B was a 52-year-old woman with an ocular history significant for bilateral vein occlusions treated with laser, and a medical history of hypertension, hyperlipidemia, and end-stage renal disease secondary to hypoplastic kidney status-post deceased donor renal transplant presented with one week of blurred vision in the right eye. Fundoscopic examination of the right eye revealed macular star configuration of exudates, as well as subretinal fibrosis temporal to the macula. Fundoscopic examination of the left eye showed Grade 4 vitreous haze and multiple areas of retinal whitening and hemorrhage, consistent with CMV retinitis infection. The patient was diagnosed with bilateral CMV retinitis, with macular involvement in the right eye. Renal transplant patients converted to belatacept immunosuppression may be at an increased risk for herpes virus infection, and thus herpes virus retinitis. Although the degree of risk remains uncharacterized, patients on belatacept therapy who are at the high risk of CMV infection (i.e., donor-positive/recipient-negative patients) should be counseled on the presenting signs and symptoms of CMV retinitis. In these cases, clinicians should also consider regular monitoring of serum CMV titers or continuation of antiviral prophylaxis.

Human Cytomegaly Virus Immunoglobulin as an Early Adjunctive Therapy Increased CMV-Free Survival after Heart Transplantation

Purpose There is still an ongoing discussion whether a prophylactic or a preemptive therapy against cytomegalovirus (CMV) is superior to reduce the incidence of CMV viremia, acute rejections (AR) or cardiac allograft vasculopathy (CAV) after heart transplantation (HTx). Thus, we evaluated different CMV treatment strategies in this setting. Methods HTx patients (n=56) were retrospectively studied regarding the end points of CMV-free survival viremia, AR, and CAV. The average follow-up was 4.15 years (355 days up to 7.5 years). Patients were classified into 3 groups according to their CMV therapy: preemptive therapy (PRE, n=19), prophylactic drug monotherapy (PROM, either valganciclovir for 3 months or early single dose of 1mg/kg/BW of CMV immunoglobulin, CMVIG, 2 weeks post-HTx, n=18) or prophylactic double drug therapy (PROD, valganciclovir for 3 months plus early single dose of CMVIG, n=19). For statistical analysis X2, X2-log-rank and T-Tests were used. Results Median patient survival was similar: PRE-group 2243 days, PROM-group 2417 days, and PROD-group 2410 days, respectively. However, the median CMV-viremia free survival was different among the groups: 1817 days in the PROD-group, 1459 days in the PROM-group and 1482 in the PRE-group (p=0.52). A subanalysis of patients with high risk for CMV infection (donor+/ recipient-CMV status) the CMV-free survival was significantly higher when patients received double prophylaxis therapy compared to the other two groups (p<0.01). Whether the incidence of AR nor of CAV was not significantly influenced by the choice of CMV treatment regimen. Antiviral medication was discontinuated in 10.5% PRE-group, 38.9% PROM-group, and 31.6% PROD-group, respectively. Conclusion Our study results suggest that early therapy with CMVIG as adjunct to antiviral treatment could prolong CMV-free survival in patients with CMV risk of infection. If a repetitive CMVIG dosing post-HTx will further reduce CMV infection needs to be explored in the future. There is still an ongoing discussion whether a prophylactic or a preemptive therapy against cytomegalovirus (CMV) is superior to reduce the incidence of CMV viremia, acute rejections (AR) or cardiac allograft vasculopathy (CAV) after heart transplantation (HTx). Thus, we evaluated different CMV treatment strategies in this setting. HTx patients (n=56) were retrospectively studied regarding the end points of CMV-free survival viremia, AR, and CAV. The average follow-up was 4.15 years (355 days up to 7.5 years). Patients were classified into 3 groups according to their CMV therapy: preemptive therapy (PRE, n=19), prophylactic drug monotherapy (PROM, either valganciclovir for 3 months or early single dose of 1mg/kg/BW of CMV immunoglobulin, CMVIG, 2 weeks post-HTx, n=18) or prophylactic double drug therapy (PROD, valganciclovir for 3 months plus early single dose of CMVIG, n=19). For statistical analysis X2, X2-log-rank and T-Tests were used. Median patient survival was similar: PRE-group 2243 days, PROM-group 2417 days, and PROD-group 2410 days, respectively. However, the median CMV-viremia free survival was different among the groups: 1817 days in the PROD-group, 1459 days in the PROM-group and 1482 in the PRE-group (p=0.52). A subanalysis of patients with high risk for CMV infection (donor+/ recipient-CMV status) the CMV-free survival was significantly higher when patients received double prophylaxis therapy compared to the other two groups (p<0.01). Whether the incidence of AR nor of CAV was not significantly influenced by the choice of CMV treatment regimen. Antiviral medication was discontinuated in 10.5% PRE-group, 38.9% PROM-group, and 31.6% PROD-group, respectively. Our study results suggest that early therapy with CMVIG as adjunct to antiviral treatment could prolong CMV-free survival in patients with CMV risk of infection. If a repetitive CMVIG dosing post-HTx will further reduce CMV infection needs to be explored in the future.

More Advanced Heart Failure Prior to Heart Transplant May Influence the Cytomegalovirus Specific T Cell Response in Cytomegalovirus Positive Recipients

Purpose Current assessment of risk of Cytomegalovirus (CMV) infection in CMV+ heart transplant (HT) recipients is poor. A diminished CMV-specific T cell response against 2 CMV antigens (IE-1 and pp65), using the IFN-γ ELISPOT, is associated with higher risk of developing CMV infection after HT. However we do not know the reasons for this diminished CMV-specific T cell response. We aimed to evaluate predictors of intermediate or high risk of developing CMV infection according to the IFN-γ ELISPOT at the time of HT. Methods We prospectively evaluated all CMV+ HT recipients in one institution from 2017 until present in whom we performed an IFN-γ ELISPOT on the day of HT. Patients were classified into low risk (IE-1>23 spots and pp65>79 spots) and not low risk: Intermediate (IE-1 Results We included 26 CMV+ HT recipients of which 14 had low risk ELISPOT and 12 not low risk ELISPOT (4 intermediate, 6 high and 2 anergic). Variables closer to HT according to the ELISPOT group are presented in the table. We included left ventricular ejection fraction (LVEF), MELD score and NTproBNP value in the multivariate analysis but none of them significantly predicted a not low risk ELISPOT. Conclusion More advanced heart failure before HT may be associated with a higher risk of CMV infection in CMV+ recipients. We need bigger numbers to confirm this tendency.

Letermovir Prophylaxis Demonstrates High Efficacy in Adult Cytomegalovirus (CMV) Seropositive Cord Blood Transplant (CBT) Recipients: A Comparison with Pre-Letermovir Era CBT Controls

Background CMV seropositive CBT recipients have a high risk of CMV infection. Early pre-emptive therapy is required to avoid CMV disease but is associated with significant toxicities. Methods This analysis compares the day +100 incidence & severity of clinically significant CMV infection (viremia leading to pre-emptive treatment or disease) in CMV seropositive CBT adult patients (pts) who received letermovir prophylaxis transplanted 12/2017-6/2018 vs historic controls transplanted 3/2013-12/2017. Control pts received ganciclovir prophylaxis days -7 to -2 then standard dose acyclovir. Letermovir pts received standard dose acyclovir & started letermovir IV or PO on day +7 & continued beyond day +100. All pts received uniform intermediate intensity Cy 50 mg/kg / Flu 150 mg/m2/ Thio 5-10 mg/kg / TBI 400 cGy conditioning with CSA/ MMF. Pts were monitored by qPCR twice weekly from approximately day +14-60 & then 1-2 x/weekly days +60-100. Results 62 [median age 51 years (range 23-66), 46 leukemia, 7 MDS/ MPD, 9 NHL/ HL] historic control pts received double unit grafts with a median unit-recipient HLA-allele match of 5/8 (range 2-7). By day +100, 51 pts developed clinically significant CMV infection for a day +100 cumulative incidence of 82% (95%CI: 70-90). The median viremia onset was 34 days (range 5-74) & 5 pts developed CMV disease by day +100 (3 pulmonary, 2 GI). Initial therapy was with foscarnet in 28 pts & ganciclovir/ valganciclovir in 23. Clinically significant therapy toxicities (renal &/or myelosuppression) were observed in 38/51 (75%) pts (Table 1). By day +100, CMV caused or contributed to 3 pulmonary deaths. 10 pts [median age 48 years (range 24-59), 9 leukemia, 1 MDS/ MPD, median 5/8 (range 3-6) unit-recipient HLA-match] received letermovir prophylaxis (8 IV, 2 PO) (Table 2). All pts engrafted. The day +100 cumulative incidence of clinically significant CMV infection was 0% (p Conclusions This analysis suggests letermovir prophylaxis is highly effective at mitigating CMV disease, CMV-related mortality, & the need for toxic CMV therapies. Moreover, it has been well tolerated in CBT recipients. While further detailed investigation in a larger population is required, this data is very promising & the extent of the benefit suggests that letermovir could be a cost-effective new standard of care in adult CBT. The duration of needed prophylaxis beyond day +100 in CBT recipients also requires investigation.

Diagnostic utility of monitoring cytomegalovirus-specific immunity by QuantiFERON-cytomegalovirus assay in kidney transplant recipients

BackgroundDespite universal prophylaxis, late cytomegalovirus (CMV) infection occurs in a high proportion of kidney transplant recipients. We evaluated whether a specific viral T-cell response allows for the better identification of recipients who are at high risk of CMV infection after prophylaxis withdrawal.MethodsWe conducted a prospective study in 19 pretransplant anti-CMV seronegative kidney graft recipients R- (18 from seropositive donors [D+] and one from a seronegative donor [D-]) and 67 seropositive recipients R(+) (59 from seropositive donors and eight from seronegative donors) who received antiviral prophylaxis with valganciclovir. The QuantiFERON-CMV (QF-CMV) assay was performed within the first and third months after transplantation. Blood samples were monitored for CMV DNAemia using a commercial quantitative nucleic acid amplification test (QNAT) that was calibrated to the World Health Organization International Standard.ResultsTwenty-one of the 86 patients (24%) developed CMV viremia after prophylaxis withdrawal within 12 months posttransplantation. In the CMV R(+) group, the QF-CMV assay yielded reactive results (QF-CMV[+]) in 51 of 67 patients (76%) compared with 7 of 19 patients (37%) in the CMV R(−) group (p = 0.001). In the CMV R(+) group, infection occurred in seven of 16 recipients (44%) who were QF-CMV(−) and eight of 51 recipients (16%) who were QF-CMV(+). In the CMV R(−) group, infection evolved in five of 12 recipients (42%) who were QF-CMV(−) and one of 7 recipients (14%) who were QF-CMV(+). No difference was found in the incidence of CMV infection stratified according to the QF-CMV results with regard to the recipients’ pretransplant CMV IgG serology (p = 0.985). Cytomegalovirus infection occurred in 15 of 36 patients (42%) with hypogammaglobulinemia (HGG) 90 days posttransplantation compared with two of 34 patients (6%) without HGG (p = 0.0004). Cytomegalovirus infection occurred in seven of 13 patients (54%) with lymphocytopenia compared with 14 of 70 patients (20%) without lymphocytopenia (p = 0.015). The multivariate analysis revealed that the nonreactive QuantiFERON-CMV assay was an independent risk factor for postprophylaxis CMV infection.ConclusionsIn kidney transplant recipients who received posttransplantation prophylaxis, negative QF-CMV results better defined the risk of CMV infection than initial CMV IgG status after prophylaxis withdrawal. Hypogammaglobulinemia and lymphocytopenia were risk factors for CMV infection.

Incidence and Risk Factors for Cytomegalovirus Infection in Patients With Kidney Transplantation: A Single-Center Experience.

Cytomegalovirus (CMV) infection is deemed to be a major cause of morbidity and mortality in patients after kidney transplantation. The purpose of this study was to analyze the incidence of CMV infection and risk factors for CMV infection in our center, to help in determination of its impact on the kidney function in this patient population, and to provide new ideas for the prevention and treatment of CMV infection. A total of 319 kidney transplant recipients from our center were studied between January 2000 and December 2015. The CMV viral load in each kidney transplant patients was monitored with the use of CMV quantitative nucleic acid testing (CMV-QNAT). Laboratory data and other medical records were also collected. The incidence of CMV infection was 8.8% in our studied patients. The patients within 3 to 6 months and 5 to 10 years after transplantation had a higher risk of CMV infection. CMV infection was probably correlated with lower white blood cell counts but elevated hemoglobin, serum creatinine, blood urea nitrogen, potassium, and estimated glomerular filtration rate (eGFR). Anti-CMV immunoglobulin (Ig)G and history of allograft rejection were also associated with CMV infection. In multivariate regression analysis, white blood cells, eGFR, anti-CMV IgG, and history of allograft rejection were the independent risk factors associated with CMV infection in kidney transplantation patients. CMV infection was an important complication after kidney transplantation, particularly in these patients with allograft impairment.

Early cytomegalovirus-specific T-cell response and estimated glomerular filtration rate identify patients at high risk of infection after renal transplantation.

Assessing the risk of cytomegalovirus (CMV) viremia in kidney transplant recipients (KTR) may be helpful to indicate in which patient it is worth starting antiviral treatment during preemptive strategy. In 40 CMV-seropositive KTR preemptively treated with ganciclovir, we used interferon (IFN)-γ ELISpot test to evaluate whether monitoring T cells directed against phosphoprotein (pp) 65 and immediate early (IE)-1 antigens could predict the onset of viremia. CMV viremia occurred in 24 patients (60%) within 120 days after transplantation. Non-viremic patients had higher anti-pp65, anti-IE-1 T cells, and estimated glomerular filtration rate (eGFR) in the first 90 days after transplantation. At logistic regression, anti-pp65, anti-IE-1 T cells, and eGFR measured at day 30 were significantly associated with CMV infection. Cutoff values of 15 spot-forming cells (SFCs)/200,000 peripheral blood mononuclear cells (PBMCs) for anti-IE, 40 SFCs/200,000 PBMCs for anti-pp65, and 46.6 mL/min/1.73 m(2) for eGFR, respectively, predicted the risk of CMV infection with high sensitivity and specificity (area under the receiver operating characteristic curve >0.75). Using a classification tree model, we identified as high-risk patients those showing anti-pp65 <42 SFCs/200,000 PBMCs and eGFR <62 mL/min/1.73 m(2) , as well as anti-pp65 ≥42 and anti-IE-1 <6.5 SFCs/200,000 PBMCs. Monitoring CMV-specific T-cell responses and eGFR in the first month post transplant can identify patients at high risk of CMV infection, for whom preemptive antiviral therapy is recommended.

Efficacy of Extended Valganciclovir Prophylaxis in Preventing Cytomegalovirus Infection in Pediatric Kidney Transplantation

Cytomegalovirus (CMV) is one of the most frequent opportunistic infection in renal transplant (RTx) recipients. Valganciclovir (VGC) has been showed to be safe and highly effective in prophylaxis of CMV infection in RTx recipients. Recently, an increase in delayed onset CMV disease has been noted with some arguing that longer prophylaxis may decrease the late-onset disease. We retrospectively tested the hypothesis that extended term prophylaxis (ETP) of VGC for 12 months is more effective than short term prophylaxis (STP) of 6 months in preventing CMV infection and disease in pediatric RTx performed at the University of Florida from July 2003 to December 2010. In this period, all recipients underwent prospective CMV PCR (Polymerase Chain Reaction) monitoring and were maintained on similar immunosuppression. Eighty six patients received RTx during that period. All eligible subjects had to have at least 12 months of graft survival and 18 months of follow up, leaving 73 eligible subjects in final study group. CMV infection or disease occurred in 6/29 (20%) in the STP group vs 6/44 (14%) in the ETP group with no statistical significant difference (P= 0.42). Donor positive/recipients negative CMV serology status (D+/R-) were associated with a higher risk of CMV infection in both univariate and multivariate analysis (P=0.01). Anemia and Leucopenia directly associated with VGC were similar in both groups (P=0.58 and P=0.2 respectively). Biopsy-proven acute rejection was also non-significant in both groups (P=0.39). Although ETP for CMV from 6 months to 12 months is safe and has minimal adverse effect, it did not reduce CMV infection or disease. Further controlled studies in pediatrics age group are considered to compare longer versus shorter periods of prophylaxis and their impact on prevention of CMV infection, resistance, cost, and toxicity.