Recurrent Cytomegalovirus Infection Research Articles

Incidence of Cytomegalovirus Infection After Repeat Keratoplasty and Associated Rate of Graft Failure.

The aim of this work was to compare the prognosis and characteristics of patients with Cytomegalovirus (CMV) infection (CMV+) with those of patients without virus infection (Virus-) undergoing repeat keratoplasty. This prospective propensity score-matched cohort study enrolled patients who underwent repeat keratoplasty for graft failure at the Peking University Third Hospital between January 2016 and May 2022. Patients with prior viral keratitis before the first keratoplasty were excluded. The primary outcome measure was the graft failure rate. The secondary outcome measures included the anterior segment characteristics, intraocular pressure (IOP), and endothelial cell density. Ninety-four matched patient pairs were included. The graft failure rate in the CMV+ group (71%) was higher than that in the Virus- group (29%) (P < 0.001). CMV infection in the cornea increased the risk of repeat graft failure and shortened the median survival time (hazard ratio, 3.876; 95% confidence intervals, 2.554-5.884; P < 0.001). The characteristics of graft failure included exacerbation of ocular surface inflammation, neovascularization, and opacification. Epithelial defects, high IOP, and endothelial decompensation were observed at an increased frequency in the CMV+ group (all P < 0.005). Recurrent CMV infection presented as early endothelial infection in the CMV+ group. Recurrence of CMV infection was confined to the graft endothelium without involving the stroma and epithelium post-repeat endothelial keratoplasty. CMV infection post-keratoplasty leads to persistent endothelial damage and graft opacification and significantly increases the risk of repeat graft failure. Localized recurrence of CMV infection in the endothelial grafts underscores the importance of monitoring and treatment. Chictr.org.cn, ChiCTR1800014684.

CMV hyperimmune globulin as salvage therapy for recurrent or refractory CMV infection in children undergoing hematopoietic stem cell transplantation.

Cytomegalovirus (CMV) is a major cause of allogeneic hematopoietic stem cell transplant (HSCT)-related morbidity and mortality. Treatment failure continues to be a major issue in patients with CMV infection due to both drug resistance and intolerance. This single-center brief retrospective analysis of a case series aims to investigate the safety and efficacy of CMV-hyperimmune globulin as salvage therapy for CMV infection in children undergoing HSCT. Fifteen pediatric patients received human CMV-specific immunoglobulin (CMVIG) between July 2018 and December 2021 as a salvage therapy for refractory or recurrent CMV infection. At the time of CMVIG prescription, eight children presented with recurrent CMV infection and seven with refractory CMV infection. The overall response rate was 67% at 50 days from the CMVIG administration [95% confidence interval (CI): 44-88]. Overall survival (OS) from CMVIG administration at 100 days was 87% (95% CI: 56-96), and OS from HSCT at 1 year was 80% (95% CI: 50-93). Four patients died, three unrelated to CMV infection and one due to CMV pneumonia. CMVIG as salvage therapy was well tolerated, and no infusion-related adverse events were observed.

215a. Use of Viracor Cytomegalovirus T-Cell Immunity Panel (TCIP) to Predict the Risk of Recurrent Cytomegalovirus Infection in Solid Transplant Patients and Guide Appropriate Management

Abstract Background Cytomegalovirus infection (CMV) is the most common opportunistic infection in solid organ transplant recipients (SOTR). Predicting recurrent disease and appropriate use of secondary antiviral prophylaxis is currently poorly defined. CMV-specific T-cell assays have been shown to be promising tools in determining presence of CMV immunity and helping guide primary and secondary antiviral prophylaxis. The goal of this study was to evaluate the ability of commercially available CMV-TCIP in predicting the risk of CMV relapse. Methods After IRB approval, clinical and laboratory data was retrospectively collected from our Enterprise Data Warehouse and primary chart review on 74 SOTR. As part of routine clinical care, the CMV T-Cell Immunity Panel (CMV-TCIP, Viracor Eurofins, Lenexa, KS) were collected by the TID provider managing the infection; generally this was done around the time of first negative test to inform choice of 2° prophylaxis. Analysis was completed for the total patient population and a subgroup of patients with CMV-TCIP tests completed ± 21 days of the first negative CMV VL. Descriptive statistics and Cohen’s Kappa statistics were used to assess association of relapse with assay results. Results Patient demographics are shown in Table 1. 2° prophylaxis was given to 60 (81.1%) of total patients for a mean of 86 days (0-614 days) after the first negative CMV VL. 26 (35.1%) SOTRs had relapse – 9 with positive CD4 and 20 with positive CD8 CMV-TCIP values. There was no association between specific test results and risk of relapse in the overall study population (see table 2). Similarly, no significance was found in the subgroup analysis of patients with CMV-TCIP results ± 21 days after first negative CMV VL. Conclusion In this study, CMV-TCIP did not predict CMV relapse after initial infection and treatment. While prior studies have shown a potential role for assessment of CMV-specific immunity to guide need for secondary prophylaxis, more studies of the CMV-TCIP are needed to assess the utility of this assay for this indication. Disclosures Michael P. Angarone, DO, Abbvie: Advisor/Consultant Valentina Stosor, MD, DiaSorin: Advisor/Consultant|Eli Lilly and Company: Grant/Research Support|Med Learning Group: Honoraria Michael G. Ison, MD MS, GlaxoSmithKlein: Grant/Research Support|Pulmocide: Grant/Research Support|Viracor Eurfins: Advisor/Consultant.

Acute cytomegalovirus infection modulates the intestinal microbiota and targets intestinal epithelial cells.

Primary and recurrent cytomegalovirus (CMV) infections frequently cause CMV colitis in immunocompromised as well as inflammatory bowel disease (IBD) patients. Additionally, colitis occasionally occurs upon primary CMV infection in patients who are apparently immunocompetent. In both cases, the underlying pathophysiologic mechanisms are largely elusive - in part due to the lack of adequate access to specimens. We employed the mouse cytomegalovirus (MCMV) model to assess the association between CMV and colitis. During acute primary MCMV infection of immunocompetent mice, the gut microbial composition was affected as manifested by an altered ratio of the Firmicutes to Bacteroidetes phyla. Interestingly, these microbial changes coincided with high-titer MCMV replication in the colon, crypt hyperplasia, increased colonic pro-inflammatory cytokine levels, and a transient increase in the expression of the antimicrobial protein Regenerating islet-derived protein 3 gamma (Reg3γ). Further analyses revealed that murine and human intestinal epithelial cell lines, as well as primary intestinal crypt cells and organoids represent direct targets of CMV infection causing increased cell death. Accordingly, in vivo MCMV infection disrupted the intestinal epithelial barrier and increased apoptosis of intestinal epithelial cells. In summary, our data show that CMV transiently induces colitis in immunocompetent hosts by altering the intestinal homeostasis.

Analysis of risk factors and prognosis of cytomegalovirus infection post umbilical cord blood stem cell transplantation in children with primary immunodeficiency diseases

Objective: To investigate the risk factors and outcomes of cytomegalovirus (CMV) infection post umbilical cord blood stem cell transplantation (UCBT) in children with primary immunodeficiency diseases (PID). Methods: Clinical data of 143 PID children who received UCBT in the Children's Hospital of Fudan University from January 2015 to June 2020 were collected retrospectively. CMV-DNA in the plasma was surveilled once or twice a week within 100 days post-UCBT. According to the CMV-DNA test results, children were divided into the CMV-infected group and the CMV-uninfected group. The incidence and risk factors of CMV infection were analyzed. At 1-month post-UCBT, the absolute lymphocyte count, ratio of lymphocyte subsets and immunoglobulin levels were compared between those whose CMV infection developed 1-month later post-UCBT and those not. Mann-Whitney U test and chi-squared test were used for comparision between groups. Kaplan-Meier survival analysis was used to analyze the impact of CMV infection on survival. Results: Among 143 patients, there were 113 males and 30 females, with a age of 14 (8, 27) months at UCBT. Chronic granulomatosis disease (n=49), very-early-onset inflammatory bowel disease (n=43) and severe combined immunodefiency (n=29) were the three main kinds of PID. The rate of CMV infection was 21.7% (31/143), and the time of infection occurring was 44 (31, 49) days post-UCBT. The incidence of recurrent CMV infection was 4.2% (6/143) and refractory CMV infection was 4.9% (7/143).There was no significant difference in the first time CMV-DNA copy and peak CMV-DNA copy during treatment between the recurrent CMV infection group and the non-recurrent CMV infection group (32.8 (18.3, 63.1)×106 vs. 22.5 (13.2, 31.9)×106 copies/L, Z=-0.95, P=0.340;35.2 (20.2, 54.6)×106 vs. 28.4 (24.1, 53.5)×106copies/L, Z=-0.10, P=0.920), so were those between the refractory CMV infection group and non-refractory CMV infection group (21.8 (13.1, 32.2)×106 vs. 25.9 (14.2, 12.2)×106copies/L, Z=-1.04, P=0.299; 47.7 (27.9, 77.6)×106 vs. 27.7 (19.7,51.8)×106copies/L, Z=-1.49, P=0.137). The CMV-infected group accepted more reduced-intensity conditioning (RIC) regimen than the CMV-uninfected group (45.2% (14/31) vs. 25.0% (28/112), χ2=4.76, P<0.05). The rate of CMV-seropositive recipients and Ⅱ-Ⅳ acute graft versus host diseases (aGVHD) are significantly higher in the CMV-infected group than the CMV-uninfected group (100% (31/31) vs. 78.6% (88/112), 64.5% (20/31) vs. 26.8% (30/112), χ2=7.98,15.20, both P<0.05). The follow-up time was 31.6 (13.2, 45.9) months, CMV infection had no effect on overall survival (OS) rate (χ2=0.02, P=0.843). There was significant difference in the survival rate among three groups of refractory CMV infection, non-refractory CMV infection and the CMV-uninfected (4/7 vs.95.8% (23/24) vs. 86.6% (97/112), χ2=5.91, P=0.037), while there was no significant difference in the survival rate among three groups of recurrent CMV infection, non-recurrent CMV infection and the CMV-uninfected (5/6 vs. 88.0% (22/25) vs. 86.6% (97/112), χ2=0.43, P=0.896). Children who developed CMV infection after 30 days post-UCBT had lower absolute count and rate of CD4+ T cells and immunoglobulin G (IgG) level than those in the CMV-uninfected group (124.1 (81.5, 167.6) ×106 vs. 175.5 (108.3, 257.2) ×106/L, 0.240 (0.164, 0.404) vs. 0.376 (0.222, 0.469), 9.3 (6.2, 14.7) vs. 13.6 (10.7, 16.4) g/L, Z=-2.48, -2.12,-2.47, all P<0.05), but have higher rate of CD8+T cells than those in CMV-uninfected group (0.418 (0.281, 0.624) vs. 0.249 (0.154, 0.434), Z=-2.56, P=0.010). Conclusions: RIC regimen, grade Ⅱ-Ⅳ aGVHD and CMV-seropositive recipients are the main risk factors associated with CMV infection in PID patients post-UCBT. Survival rate of children with refractory CMV infection after UCBT is reduced. Immune reconstitution in children after UCBT should be regularly monitored, and frequency of CMV-DNA monitoring should be increased for children with delayed immune reconstitution.

P8.152: Clinical Characteristics and Factors Related to Recurrent Cytomegalovirus Infection Post-kidney Transplant in Adult Patients at Cho Ray Hospital

Introduction: Cytomegalovirus (CMV) is one of the main causes of opportunistic infections after kidney transplantation. Manifestations of CMV disease in post renal transplantation patients are quite discreet, non-specific and difficult to diagnose early. Asymptomatic recurrent CMV infection has been reported remarkably to increase mortality rate and rejection incidence, and effect on graft survival. The recently follow-up and treatment procedures’ changes make it urgent to re-evaluate the incidence and the factors related to the risk of CMV recurrence as well as the clinical characteristics of CMV infection in postkidney transplantation patients. This helps to control the recurrence of CMV infection as well as to diagnose CMV disease early and treat it promptly and appropriately to reduce the mortality rate of patients after transplantation. Method: Objective 1: Retrospective cohort study of adult renal transplant recipients between January 1, 2015 and December 31, 2018. Objective 2: A cross - sectional descriptive study on 22 cases of CMV disease in post kidney transplant patients to present a review of the main clinical aspects of cytomegalovirus infection in renal transplants with a focus on clinical approach and its future perspectives. Results: Objective 1: A total of 365 patients who received a renal transplant at Cho Ray hospital in the study time period were reviewed for the presence of CMV infection occurring less than 540 days after transplant. The recurrent CMV infection was observed in 254 cases (69,6%), but only 3 patients (0,8%) developed CMV disease. Independent risk factors of CMV infection were HLA >80 (HR = 2,309, 95% CI 1,021 – 4,071, p = 0,044), daily oral Prednisone doses used <0,5 mg/kg/day (HR = 0,178, 95% CI 0,084 – 0,374, p <0,001), Tacrolimus whole blood trough concentration ≤10 µg/L (HR = 0,445, 95% CI 0,243 – 0,816, p = 0,009), Cyclosporine wole blood trough concentration >150 µg/L (HR = 4,25, 95% CI 1,97 – 9,2, p < 0,001). Objective 2: Male majority (2/3), with average age of 47,5 ± 4,5. Rate of symptomic recurrence CMV infection in the first 6 months, 6 - 12 months, 1 - 5 years, 5 - 10 years after transplant were 45,4%, 9,1%, 27,3% and 18,2% respectively. Common clinical manifestations are fever 59,1%, respiratory, renal and gastrointestinal manifestations 31,8%, 27,3% and 13,6%, respectively. Two cases of CMV retinitis with typical fundus lesions were treated with intraocular Ganciclovir, however, vision was not fully recovered. Lymphopenia <1.000 cells/mm3 was observed in most cases of CMV disease after kidney transplantation. Quantitative PCR of CMV DNA in plasma ranged from 375 – 6.533.850 copies/mL. 6 of 22 cases of PCR CMV DNA in plasma >4.000 copies/mL, of which 5 severe cases developed rapidlly progressive respiratory failure and 2 deaths. Conclusion: Recurrent CMV infection has a high rate in adult patients after kidney transplantation, so it is necessary to take initiactive for screening, monitoring and treating early to reduce mortality and protect the transplanted kidney. The appropriate dose of immunosuppressants plays an important role in the prevention of recurrent CMV infection and the successful treatment of disease due to it. Key words: Cytomegalovirus, Kidney transplantation, Post-transplant infection. * Deparment of Tropical diseases– Cho Ray Hospital ** Nephrology Surgery – Cho Ray Hospital Coresponding author: Tho A. N. Vo, Deparment of Tropical diseases– Cho Ray Hospital. Email: [email protected]. Mobile: 0983888841.

Polygenic Innate Immunity Score to Predict the Risk of Cytomegalovirus Infection in CMV D+/R- Transplant Recipients. A Prospective Multicenter Cohort Study.

Several genetic polymorphisms of the innate immune system have been described to increase the risk of cytomegalovirus (CMV) infection in transplant patients. The aim of this study was to assess the impact of a polygenic score to predict CMV infection and disease in high risk CMV transplant recipients (heart, liver, kidney or pancreas). On hundred and sixteen CMV-seronegative recipients of grafts from CMV-seropositive donors undergoing heart, liver, and kidney or pancreas transplantation from 7 centres were prospectively included for this purpose during a 2-year period. All recipients received 100-day prophylaxis with valganciclovir. CMV infection occurred in 61 patients (53%) at 163 median days from transplant, 33 asymptomatic replication (28%) and 28 CMV disease (24%). Eleven patients (9%) had recurrent CMV infection. Clinically and/or functionally relevant single nucleotide polymorphisms (SNPs) from TLR2, TLR3, TLR4, TLR7, TLR9, AIM2, MBL2, IL28, IFI16, MYD88, IRAK2 and IRAK4 were assessed by real time polymerase chain reaction (RT-PCR) or sequence-based typing (PCR-SBT). A polygenic score including the TLR4 (rs4986790/rs4986791), TLR9 (rs3775291), TLR3 (rs3775296), AIM2 (rs855873), TLR7 (rs179008), MBL (OO/OA/XAO), IFNL3/IL28B (rs12979860) and IFI16 (rs6940) SNPs was built based on the risk of CMV infection and disease. The CMV score predicted the risk of CMV disease with an AUC of the model of 0.68, with sensitivity and specificity of 64.3 and 71.6%, respectively. Even though further studies are needed to validate this score, its use would represent an effective model to develop more robust scores predicting the risk of CMV disease in donor/recipient mismatch (D+/R-) transplant recipients.

Recurrent Cytomegalovirus Infection Controlled by the Introduction of Everolimus in a Simultaneous Pancreas-Kidney Transplantation Recipient: A Case Report

In simultaneous pancreas-kidney transplantation (SPK) recipients, cytomegalovirus (CMV) infection is a major complication that has been associated with the use of tacrolimus (TAC)-based immunosuppression. As one of the immunosuppressive drug options, the use of mammalian target of rapamycin inhibitors (mTORi) results in reduced rates of CMV infection in the field of solid organ transplantation. However, little is known about mTORi usage in pancreas transplantation. We report a case of recurrent CMV infection that was controlled by the introduction of mTORi (everolimus) in addition to a TAC-based immunosuppression regimen in SPK. A 52-year-old man underwent SPK. Graft duodenal perforation occurred on the 13th day of surgery, and graft duodenal resection was performed after long-term abscess drainage treatment. After graft duodenal resection, he was diagnosed with CMV viremia, and valganciclovir was started. However, because of recurrent febrile neutropenia caused by cytopenia as a side effect of valganciclovir, there was a repeated need for granulocyte-colony stimulating factor treatment. Immunosuppressive drug taper adjustment was attempted to control recurrent CMV viremia, and everolimus was introduced with the aim of reducing the dose of TAC and mycophenolate mofetil. This resulted in a continuously negative CMV antigenemia test and a stable general condition. Understanding the characteristics of various immunosuppressive agents and appropriately controlling and managing infectious diseases is crucial for the good postoperative management of patients with SPK.

Does the cytomegalovirus infection cause kidney transplant rejection in Erbil city patients, Kurdistan region of Iraq?

Does the cytomegalovirus infection cause kidney transplant rejection in Erbil city patients, Kurdistan region of Iraq?

Risk factors and outcomes of cytomegalovirus infection in children post cord blood transplantation with focus on impact of graft-versus-host disease and immunosuppressants.

Cytomegalovirus (CMV) infection remains an important cause of morbidity and mortality post cord blood transplantation (CBT). It has been suggested that the graft-versus-host disease (GVHD) and immunosuppressants have an impact on CMV infection. This study evaluated the incidence, outcomes, and risk factors of CMV infection, while focusing on GVHD and the use of immunosuppressants, in 103 children who had received CBT. Among the patients, 92.2% were positive for CMV serology, while CMV antigenemia was observed in 68.9% and CMV disease developed in 26.2%. CMV enterocolitis was the most common, followed by retinitis and pneumonia. Patients with positive CMV serology and grade II to IV GVHD were independently associated with CMV antigenemia. Recurrent CMV antigenemia was observed significantly more frequently in patients with extensive chronic GVHD. Patients with CMV disease showed significantly worse overall survival, relapse-free survival, and non-relapse mortality than those without CMV disease. In conclusion, CMV infection is common post-CBT in countries with a high rate of CMV seropositivity in the general population and is related to worse outcomes. GVHD severity is associated with the development and recurrence of CMV infection. Thus, efforts need to be made to prevent CMV infection in children post-CBT.

T cell receptor beta locus sequencing early post-allogeneic stem cell transplant identifies patients at risk of initial and recurrent cytomegalovirus infection.

Identification of patients at risk of initial & recurrent cytomegalovirus (CMV) reactivation following allogeneic stem cell transplant (alloSCT) may help guide prophylactic strategies. T-cell receptor beta (TRB) deep sequencing was used to identify and enumerate the T-cell repertoire harbouring TRB sequences with annotated specificity to CMV (pubCMVrep), as well as the overall T-cell receptor (TCR) repertoire diversity at day +30 & day +60 post-alloSCT for 65 patients. T-cells harbouring TRB sequences with annotated specificity for CMV were identifiable in all patients. 56% of patients required CMV treatment and 23% of the cohort developed recurrent CMV. PubCMVrep size at day +30 was not associated with reactivation, however amongst patients with antecedent CMV viremia a low day +60 pubCMVrep was associated with a greater incidence of recurrent CMV (75% vs. 21%, HR 6.16, 95% CI 1.29-29.40, P = 0.0008). Moreover, patients with high pubCMVrep only developed recurrent CMV in the setting of GVHD. Low TCR diversity at day +30 was associated with a greater incidence of initial CMV reactivation (71% vs. 22%, HR 5.39, 95% CI 1.70-17.09, p = 0.0002). pubCMVrep and TCR diversity are promising biomarkers to identify patients at risk of initial & recurrent CMV who may benefit from novel prophylactic strategies.

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

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

A single-centre observational study comparing the impact of different cytomegalovirus prophylaxis strategies on cytomegalovirus infections in kidney transplant recipients

Background/objective: Prevention of cytomegalovirus (CMV) infection is an important component of post kidney transplant care. We aimed to evaluate the impact of two different CMV prophylaxis protocols on the epidemiology and outcomes of CMV infections at our centre. Methods: This is a single-centre retrospective before/after observational study. Kidney transplant recipients who received Protocol 1, a valacyclovir- or valganciclovir-based regimen prescribed for one to three months based on the CMV risk status between 2004 and 2008, were compared to those who received Protocol 2, a valganciclovir-based regimen prescribed for three months and six months for those at moderate and high risk, respectively, between 2010 and 2014. The impact of different prophylaxis regimens on the incidence of CMV infections, disease, recurrent infections and onset of CMV infection at 24 months were reviewed. Results: There were 192 patients included; 106 patients received Protocol 1, 86 received Protocol 2. At 24 months, the incidence of CMV infection was 53.8% and 55.8% in Protocols 1 and 2, respectively ( p=0.884). The incidence rates of CMV disease and recurrent CMV infections were higher in Protocol 1, but this was not statistically significant. The median time to first CMV infection was significantly shorter in patients who received Protocol 1: 132 days (interquartile range (IQR) 125–139 days) versus 185 days (IQR 178–192 days), p=0.001. Both prophylaxis protocols were well tolerated. Conclusion: The incidence of CMV infection was similar in both protocols. Where valganciclovir is not available, valacyclovir may be considered over no prophylaxis. Post-prophylaxis CMV infections are not uncommon, and vigilance for it should be advocated.

Drug Resistance Mutations and Associated Phenotypes Detected in Clinical Trials of Maribavir for Treatment of Cytomegalovirus Infection.

BackgroundIn separate phase 2 trials, 120 patients received maribavir for cytomegalovirus (CMV) infection failing conventional therapy (trial 202) and 119 received maribavir for asymptomatic infection (trial 203). Overall, 172 cleared their CMV infection (CMV DNA <200 copies/mL) within 6 weeks.MethodsBaseline and posttreatment plasma samples were tested for mutations in viral genes UL97, UL54, and/or UL27. Selected viral mutants were phenotyped for drug susceptibility.ResultsBaseline samples revealed UL54 mutations newly phenotyped as conferring resistance to standard DNA polymerase inhibitor(s), including K493N, P497S, K513T, L565V, V823A, A987V, and E989D. Of 29 patients (including 25 from trial 202) who cleared but later experienced recurrent CMV infection while on maribavir, 23 had available UL97 genotyping data; 17 had known resistance mutations (T409M or H411Y) and 5 additional had UL97 C480F alone. The newly phenotyped mutation C480F conferred high-grade maribavir resistance and low-grade ganciclovir resistance. Among 25 who did not respond to >14 days of therapy, 9 showed T409M or H411Y and 4 others showed C480F alone.ConclusionsAfter maribavir therapy (400–1200 mg twice daily), UL97 mutations T409M, H411Y, or C480F emerge to confer maribavir resistance in patients with recurrent CMV infection while on therapy or no response to therapy.Clinical Trials RegistrationNCT01611974 and EudraCT 2010-024247-32.

Viral Reactivation after T Cell Replete Haploidentical Stem Cell Transplantation: Increased Incidence in Association with Immune Reconstitution

Feasibility of haploidentical stem cell transplantation (haploSCT) is enhanced by use of post-transplant cyclophosphamide (PTCY). Despite preservation of non-alloreactive T cells, delayed reconstitution of cellular immunity and viral reactivation may compromise the outcome of T cell replete haploSCT. The study included 47 patients, aged 19-70 (median, 53) years, who underwent haploSCT with PTCY for myeloid (n=35) or lymphoid (n=12) malignancies. Myeloablative conditioning was mainly utilized (n=36). Graft source was peripheral blood (n=29) or bone marrow (n=18). Cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus-6 (HHV-6) reactivation was monitored by real-time quantitative PCR (RQ-PCR) in plasma and/or leukocytes weekly for at least 6 months. BK virus (BKV) reactivation was assessed by RQ-PCR in urine and/or blood in cases with hemorrhagic cystitis (HC). Preemptive therapy was the principal modality for CMV infection in all but 1 patient who received letermovir prophylaxis. Reconstitution of cellular immunity was assessed by flow cytometry. With a median follow-up of 30 months, cumulative incidences (CIN) of relapse and non-relapse mortality were 13.4% (95% CI, 5.4-25.1%) and 31.4% (95% CI, 18.3-45.4%) at 2 years, respectively. Disease-free and overall survival were 55.2% (95% CI, 42.3-72.1%) and 61.8% (95% CI, 48.9-78.1%) at 2 years, respectively. CIN of CMV reactivation (>100 copies/ml) plateaued at 75.6% (95% CI, 60.1-85.7%) at 3 months. CMV infection developed in 34/45 patients at risk. Recurrent CMV infection occurred in 17/34 with median 1.5 (range, 1-6) episodes per patient. Median duration of anti-CMV therapy was 27 (range, 14-199) days. CMV disease was documented in 2 patients. CIN of EBV reactivation (>1,000 copies/ml) was 47.1% (95% CI, 34.2-63.9%) at 1 year, and preemptive therapy with rituximab was required in 2 patients. HHV-6 reactivation (>1,000 copies/ml) was observed in 6 patients (CIN, 10.6% at 6 months; 95% CI, 3.8-21.4%). CIN of BKV-related HC reached 27.7% (95% CI, 15.7-40.9%) at 3 months. Cystoscopy was required in 5/13 and nephrostomy in 1/13 patients. Reconstitution of T cell immunity was considerably delayed, with median CD4+ cell counts of 83/uL (range, 7-337), 216/uL (range, 80-509), and 236/uL (range, 97-586) at 3, 6 and 12 months, respectively. Recurrent CMV infection was associated with the recovery of CD4+ cells at 3 months (Figure, median CD4+ count of 191/uL versus 62/uL in patients with 1 or ³2 episodes of CMV reactivation, respectively; p=0.009). Haplo-SCT with PTCY is associated with substantial rates of viral reactivation resulting in the need for prolonged antiviral therapy and considerable morbidity as well. Strategies to prevent viral infection are strongly warranted. The timing and duration of such interventions (like letermovir or adoptive immunotherapy) may be guided by the tempo of immune reconstitution.

Alterations in NKG2A and NKG2C Subsets of Natural Killer Cells Following Epstein–Barr Virus Reactivation in CTLA4Ig-based Haploidentical Transplantation Is Associated With Increased Chronic Graft-Versus-Host Disease

The impact of newer approaches to haploidentical transplantation on Epstein-Barr virus (EBV) is largely unknown. We prospectively evaluated the incidence of EBV reactivation and its impact on transplantation outcomes in 71 patients undergoing haploidentical transplantation with posttransplantation cyclophosphamide in combination with CTLA4Ig-based T-costimulation blockade. Eight patients developed EBV reactivation at a median of 96 days with no incidence of lymphoproliferative disorder. There was no impact of EBV reactivation on acute graft-versus-host disease (GVHD), nonrelapse mortality, progression-free, or overall survival. Despite an overall incidence of 19%, there was a significant increase in chronic GVHD following EBV reactivation (62.5% versus 8%; P = 0.01). NKG2A subset of CD56 natural killer cells increased substantially and persisted following EBV reactivation and chronic GVHD, with a reciprocal decrease in NKG2C subset, whereas the reverse was witnessed in those without chronic GVHD (P < 0.01). Increase in NKG2C subset and a decrease in the NKG2A subset were witnessed within 3 months of subsidence of chronic GVHD. Thus, CTLA4Ig-based haploidentical transplantation was associated with a low incidence of EBV reactivation without EBV-lymphoproliferative disorder. However, EBV reactivation was associated with a sustained alteration in NKG2A and NKG2C subsets of CD56 natural killer cells which might have a pathogenic role in chronic GVHD.

Increased Incidence of Viral Reactivation after T Cell Replete Haploidentical Stem Cell Transplantation in Association with Delayed Immune Reconstitution

Introduction: The preferred method for haploidentical stem cell transplantation (haploSCT) is currently the use of post-transplantation cyclophosphamide (PTCY) since it obviates the need for depletion of T lymphocytes, which is associated with profound immunosuppression. Despite preservation of non-alloreactive donor T cells, reconstitution of pathogen-specific immunity may be delayed even after T cell replete haploSCT. The incidence and clinical sequelae of viral reactivation may thus compromise the outcomes of the procedure. Patients and Methods: The study included 47 patients, who underwent haploSCT with PTCY from 12/2013 until 05/2019 and achieved stable donor engraftment. Median age at transplant was 53 years (range, 19-70). The indications for transplant were acute myeloid (n=19) or lymphoblastic (n=10) leukemia, myelodysplastic syndrome (n=10), myelofibrosis (n=4), chronic myeloid (n=2) or lymphocytic (n=1) leukemia, and T-prolymphocytic leukemia (n=1). Myeloablative conditioning was mainly utilized (n=36), with the exception of certain patients who received reduced-intensity (n=10) or non-myeloablative (n=1) regimens. The graft source was peripheral blood in 29 and bone marrow in 18 cases. Tacrolimus in combination with mycophenolate mofetil was administered for prevention of graft-versus-host disease. Recipient/donor cytomegalovirus (CMV) serostatus was -/- (n=2), -/+ (n= 5), +/- (n=11), or +/+ (n=29). CMV, Epstein-Barr virus (EBV), and human herpesvirus-6 (HHV-6) reactivation was monitored by real-time quantitative PCR (RQ-PCR) in plasma and/or leukocytes weekly for at least 6 months post haploSCT. BK virus (BKV) reactivation was assessed by RQ-PCR in urine and/or blood specimens in cases with symptoms suggestive of hemorrhagic cystitis (HC). Prophylaxis with letermovir was available in 1 patient only, and preemptive antiviral therapy was the principal modality for the management of CMV infection. Cellular immunity reconstitution was assessed by flow cytometry at 3, 6, and 12 months after transplant. Results: With a median follow-up time of 30 months (range, 2-64), the cumulative incidences (CIN) of relapse and non-relapse mortality (NRM) were 13.4% (95% confidence interval [CI], 5.4-25.1%) and 31.4% (95% CI, 18.3-45.4%) at 2 years, respectively. Disease-free (DFS) and overall survival (OS) were 55.2% (95% CI, 42.3-72.1%) and 61.8% (95% CI, 48.9-78.1%) at 2 years, respectively. The CIN of CMV reactivation (&gt;100 copies/ml) plateaued at 75.6% (95% CI, 60.1-85.7%) at 3 months. CMV infection developed in 34 out of 45 patients who were at risk, whereas recurrent CMV reactivation was observed in 17 patients with a median number of 1.5 episodes (range, 1-6) per patient. The median total duration of antiviral therapy for CMV infection was 27 days (range, 14-199). CMV disease (pneumonia) was documented in 2 patients. The CIN of EBV reactivation (&gt;1,000 copies/ml) was 47.1% (95% CI, 34.2-63.9%) at 12 months. No case of EBV-related post-transplant lymphoproliferative disorder was observed, however preemptive therapy with rituximab was required in 2 patients with rapidly increasing EBV viral load. HHV-6 reactivation (&gt;1,000 copies/ml) was observed in 6 patients (CIN, 10.6% at 6 months; 95% CI, 3.8-21.4%), but only one required therapy with foscarnet due to high viral load (&gt;10,000 copies/ml). The CIN of BKV-related HC reached 27.7% (95% CI, 15.7-40.9%) at 3 months. Cystoscopy for bladder hemostasis was required in 5/13 and nephrostomy in 1/11 patients with HC. Reconstitution of helper T cell immunity was considerably delayed, with median absolute CD4+ cell counts of 83/uL (range, 7-337), 216/uL (range, 80-509), and 236/uL (range, 97-586) at 3, 6 and 12 months, respectively. Recurrent CMV infection was significantly associated with the recovery of CD4+ cells at 3 months (Figure; median CD4+ count of 191/uL versus 62/uL in patients with 1 and 2 or more episodes of CMV reactivation, respectively; p=0.009). Conclusions: HaploSCT with PTCY is associated with substantial rates of viral reactivation (especially CMV and BKV) resulting in the need for prolonged antiviral therapy and considerable morbidity. Strategies to prevent viral infection are strongly warranted in haploidentical stem cell transplantation. The timing and duration of such interventions (like letermovir or adoptive immunotherapy) may be guided by the tempo of immune reconstitution following haploSCT. Figure Disclosures Tsonis: Gilead: Other: Travel Grant; Astellas: Other: Travel Grants; Gilead: Other: Travel Grant; Aenorasis: Other: Travel Grant; Takeda: Other: Travel Grant; Pfizer: Other: Travel Grant; Innovis: Other: Travel Grant.

The impact of recurrent cytomegalovirus infection on long-term survival in solid organ transplant recipients.

Cytomegalovirus (CMV) remains a significant contributor to morbidity and mortality following solid organ transplantation (SOT). While recurrent infection occurs in up to 30% of patients, its impact on mortality is unclear. The aim of this study was to explore the relationship between recurrent CMV infection and long-term survival in SOT recipients. We performed a retrospective cohort study of SOT recipients who completed treatment for an episode of CMV infection. Patients were followed until death, loss to follow-up or 10years following CMV treatment completion. Univariable and multivariable hazard ratios (HR) were calculated, treating relapse and rejection following CMV as time-varying. About 79 kidney, 52 heart, 34 liver, and 5 liver-kidney transplant recipients were included. About 62/170 died, at a median of 3.8years (IQR 0.8-6.6years). Median follow-up among the 108 survivors was 7.4years (IQR 3.7-10years). Recurrent CMV infection occurred in 49/170 (29%), 67% within 6months of treatment completion. Mortality among those who relapsed was 39% (19/49) vs 36% (43/121) in those who remained relapse-free (unadjusted HR 1.59, 95% CI 0.92-2.75, P=.10). After adjusting for age and transplanted organ, findings were similar (HR 1.68, 95% CI 0.93-3.04, P=.09). Mortality following CMV remains high even in the valganciclovir era. Although our findings suggest a possible increased risk of death among patients with recurrent CMV, these did not reach statistical significance. The complex nature of these patients, multiple potential confounders, and limited statistical power made detection of small effects difficult. Larger prospective studies evaluating the clinical impact of strategies to reduce recurrence are needed.

Maribavir for Preemptive Treatment of Cytomegalovirus Reactivation

BackgroundMaribavir is a benzimidazole riboside with activity against cytomegalovirus (CMV). The safety and efficacy of maribavir for preemptive treatment of CMV infection in transplant recipients is not known.MethodsIn a phase 2, open-label, maribavir dose–blinded trial, recipients of hematopoietic-cell or solid-organ transplants (≥18 years of age, with CMV reactivation [1000 to 100,000 DNA copies per milliliter]) were randomly assigned to receive maribavir at a dose of 400, 800, or 1200 mg twice daily or the standard dose of valganciclovir for no more than 12 weeks. The primary efficacy end point was the percentage of patients with a response to treatment, defined as confirmed undetectable CMV DNA in plasma, within 3 weeks and 6 weeks after the start of treatment. The primary safety end point was the incidence of adverse events that occurred or worsened during treatment.ResultsOf the 161 patients who underwent randomization, 159 received treatment, and 156 had postbaseline data available — 117 in the maribavir group and 39 in the valganciclovir group. The percentage of patients with postbaseline data available who had a response to treatment within 3 weeks was 62% among those who received maribavir and 56% among those who received valganciclovir. Within 6 weeks, 79% and 67% of patients, respectively, had a response (risk ratio, 1.20; 95% confidence interval, 0.95 to 1.51). The percentages of patients with a response to treatment were similar among the maribavir dose groups. Two patients who had a response to treatment had a recurrence of CMV infection within 6 weeks after starting maribavir at a dose of 800 mg twice daily; T409M resistance mutations in CMV UL97 protein kinase developed in both patients. The incidence of serious adverse events that occurred or worsened during treatment was higher in the maribavir group than in the valganciclovir group (52 of 119 patients [44%] vs. 13 of 40 [32%]). A greater percentage of patients in the maribavir group discontinued the trial medication because of an adverse event (27 of 119 [23%] vs. 5 of 40 [12%]). A higher incidence of gastrointestinal adverse events was reported with maribavir, and a higher incidence of neutropenia was reported with valganciclovir.ConclusionsMaribavir at a dose of at least 400 mg twice daily had efficacy similar to that of valganciclovir for clearing CMV viremia among recipients of hematopoietic-cell or solid-organ transplants. A higher incidence of gastrointestinal adverse events — notably dysgeusia — and a lower incidence of neutropenia were found in the maribavir group. (Funded by ViroPharma/Shire Development; EudraCT number, 2010-024247-32.)