CMV Treatment Research Articles

Risk factors and clinical outcomes of cytomegalovirus infection following haploidentical hematopoietic stem cell transplantation in patients with aplastic anemia: a single-center retrospective study

BackgroundCytomegalovirus (CMV) infection remains a critical cause of mortality after allogeneic hematopoietic stem cell transplantation, despite significant advancements in CMV prevention and treatment with the introduction and widespread use of letermovir. However, in China, due to limitations in the availability and cost of medications, some patients still face challenges in accessing letermovir. For this subset of the population, exploring the risk factors for CMV infection remains significant in predicting its occurrence.MethodsTherefore, a retrospective analysis was conducted on 88 haploidentical hematopoietic stem cell transplant recipients over 4 years.ResultsOur study results indicate that chronic graft-versus-host disease (cGVHD) is an independent risk factor for CMV infection following haploidentical hematopoietic stem cell transplantation (Haplo-HSCT). Survival analysis reveals lower survival rates in the refractory CMV infection (RCI) group compared to the non-RCI group, with patients having lower viral loads demonstrating higher rates of seroconversion and improved survival under the same treatment regimen.ConclusionStrengthening the monitoring of CMV-DNA in post-transplant patients, actively promoting hematopoietic recovery, preventing the occurrence of CMV infection, and controlling the development of CMV infection can lead to better survival outcomes for patients with aplastic anemia undergoing Haplo-HSCT.

Individualizing Treatment for CMV with UL97 del597-599 Mutation: Beyond Unusual Response to a Lower Ganciclovir Dose Increase

Individualizing Treatment for CMV with UL97 del597-599 Mutation: Beyond Unusual Response to a Lower Ganciclovir Dose Increase

Analysis of spontaneous cytomegalovirus clearance after low level reactivation using a pre-emptive treatment threshold of 4,000 IU/mL in allogeneic hematopoietic cell transplant recipients

BackgroundCytomegalovirus (CMV) can be a serious complication after allogeneic hematopoietic cell transplant (HCT). CMV viral load is routinely monitored, and pre-emptive therapy is initiated to prevent CMV viremia from developing into CMV organ disease based on institutional thresholds. There is no established universal threshold for pre-emptive therapy and many centers utilize different strategies. MethodsAllogeneic HCT recipients at WVU Medicine from 2009 to 2021 were routinely initiated on pre-emptive CMV treatment for a PCR viral threshold above 4000 IU/mL. Adult patients with quantifiable values below this threshold, were analyzed to evaluate the rate of spontaneous clearance without initiation of CMV-directed therapy, during their first episode of CMV reactivation. This study excluded any patients that received letermovir prophylaxis. ResultsSixty patients were included in the analysis. The spontaneous clearance rate was 60 %. The risk factors that were associated with a lower spontaneous clearance rate were reactivation within thirty days after transplant (p = 0.031), presence of graft-versus-host-disease (p = 0.031), and CMV PCR values of 2500–4000 IU/mL (p = 0.02). Although these patients had lower rates of spontaneous clearance, they still spontaneously cleared in 42 %, 42 %, and 43 % of the cases, respectively. ConclusionDelaying pre-emptive treatment until a CMV PCR value of 4000 IU/mL is reached appears appropriate and decreases unnecessary treatment toxicity and resistance.

Postnatal cytomegalovirus infection and pulmonary vascular disease in extremely premature infants: A case series.

Pulmonary vascular disease (PVD) is a major determinant of both morbidity and mortality in extremely low birth weight infants. It is biologically plausible that postnatal cytomegalovirus (pCMV) infection may lead to PVD in premature infants secondary to pneumonitis or via derangement of pulmonary vascular development directly through endothelial dysfunction. Uncertainty remains, however, regarding thresholds for intervention in premature infants with cardiorespiratory instability and presumed CMV infection likely secondary to the limited understanding of the natural history of the disease. We describe four cases of premature infants with clinical and echocardiography features of PVD, in the setting of postnatally acquired CMV. All patients had atypical PVD trajectories, refractory to vasodilator treatment, which improved after initiation of CMV treatment. We highlight the need to consider postnatally acquired CMV infection in patients with PVD non-responsive to standard pulmonary vasodilator therapies or disease severity which is out of proportion of the usual clinical trajectory. Treatment of extremely premature infants with CMV-associated PVD may have positive impact on cardiorespiratory health, although duration of therapy remains uncertain.

Letermovir for Cytomegalovirus infection in pediatric patients undergoing allogenic hematopoietic stem cell transplantation: a real-life study by the Infectious Diseases Working Group of Italian Association of Pediatric Hematology-Oncology (AIEOP).

Letermovir prophylaxis revolutionized the approach to Cytomegalovirus infection in adult hematopoietic stem cell transplant (HCT), while data in pediatric setting are still lacking. We retrospectively analyzed 87 HCT children transplanted in 11 AIEOP centers receiving letermovir as off-label indication between January 2020 and November 2022. Letermovir was used as primary, secondary prophylaxis or CMV treatment in 39, 26 and 22 cases, respectively; no discontinuation due to toxicity was reported. Median duration was 100 days (14-256) for primary and 96 days (8-271) for secondary prophylaxis, respectively. None of the patients experienced CMV-clinically significant reactivation during Letermovir primary prophylaxis; one patient developed breakthrough infection during secondary prophylaxis, and 10 and 1 patient experienced asymptomatic CMV-reactivation and CMV-primary infection after drug discontinuation, respectively. Median duration of letermovir in CMV treatment was 40 days (7-134), with 4/22 patients suffering CMV-pneumonia, with an overall response rate of 86.4%. With a median follow-up of 10.7 months (8.2-11.8), estimated 1-year overall survival was 86%; no CMV-related deaths were reported in prophylaxis groups. This is the largest report on Letermovir use in pediatric HCT; real-life data confirm an excellent toxicity profile, with high efficacy as CMV prophylaxis; results in CMV-infection treatment should be investigated in larger, prospective trials.

2740. Letermovir for the Prevention and Treatment of Cytomegalovirus Infection in Solid Organ Transplant Recipients

Abstract Background Cytomegalovirus (CMV) is a common infection that can lead to end-organ damage and graft rejection in solid organ transplant (SOT) recipients. Due to the increase in drug-resistant CMV and unfavorable side effect profile of available CMV-active agents, there is a need for additional prophylactic and treatment strategies in this patient population. The goal of this study is to evaluate SOT recipients prescribed letermovir for prophylaxis and/or treatment of CMV. Methods This study was a retrospective review of adult SOT recipients in the Cleveland Clinic Health System prescribed letermovir from 11/8/2017 to 8/1/2022. The primary objective was to describe the utilization of letermovir in SOT recipients. Secondary objectives included: proportion of SOT recipients that experienced CMV breakthrough on letermovir prophylaxis, proportion of SOT recipients that experienced refractory CMV infection on letermovir treatment, prevalence of letermovir resistance, and letermovir-induced adverse effects. Results A total of 45 patients were included in the study, with 52 letermovir courses. Lung was the most commonly transplanted organ (35%), followed by kidney (22%). 78% of patients were high-risk CMV and the most common immunosuppression regimen consisted of a calcineurin inhibitor in combination with a corticosteroid (82%). 11 patients received letermovir for primary CMV prophylaxis, with only one patient experiencing new/worsening viremia while on the agent. Of the 34 patients who received letermovir for secondary CMV prophylaxis, 11 experienced new/worsening viremia. 7 patients received letermovir for CMV treatment, at a median viral load of 991 IU/mL (IQR 603-2,738) on initiation and peak viral load of 3,892 IU/mL (IQR 1,407-10,209) while on therapy. No patients in the treatment group experienced refractory infection. 7/52 (13.5%) letermovir courses were discontinued due to new/worsening viremia, with no letermovir resistance identified. No letermovir-related adverse effects were documented. Conclusion Our study shows that letermovir appears to be effective in suppressing CMV viremia. Letermovir may be an alternative option for SOT recipients who are unable to tolerate or have resistance to traditional CMV therapeutics. Disclosures All Authors: No reported disclosures

Significance of CMV reactivation in non-allogeneic stem cell transplant patients with cancers: experience of single tertiary care cancer institute.

CMV reactivation is rare in hematological as well as solid organ malignancies in non-allogeneic stem cell transplant settings. An increasing number of patients undergoing active treatment or follow-up and diagnosed with CMV reactivation in recent years prompted us to investigate the risk factors and outcomes of CMV reactivation or disease. This was a hospital-based retrospective study that included 174 cancer patients suspected of CMV reactivation. Among them, forty-one tested positive for CMV viremia. The risk factors for CMV reactivation included the use of steroids in 78% of patients, active cancer in 43.9%, use of a monoclonal antibodyrituximabin 31.7%,a history of radiation in 26.8%, and autologous stem cell transplant in 12% of patients. The median age was 36 years, and the most common clinical feature was fever (58.5%; n = 24), followed by GI symptoms (12.1%; n = 5), respiratory symptoms (14.6%; n = 6), cytopenia (7.3%; n = 3), and visual/neurological symptoms (4.8%; n = 2). The mean CMV viral load was 37,332 copies/ml (range: 75.00-633,000.00 copies/ml). Nineteen patients received CMV treatment with an average treatment duration of 81.5 days. The median overall survival was 2 months, with 12.0% of patients alive at 5 years. CMV reactivation is associated with significant morbidity and mortality. We recommend vigilant monitoring of CMV-related symptoms, with a low threshold for testing and treatment, for patients with multiple risk factors for CMV reactivation.

Overlapping Infection by Strongyloides spp. and Cytomegalovirus in the Immunocompromised Host: A Comprehensive Review of the Literature.

Strongyloides and cytomegalovirus co-infections are rarely reported, even though they are distinguished by high morbidity and mortality, especially in immunocompromised hosts. We narratively reviewed the literature on reported cases of Strongyloides and CMV co-infections in immunosuppressed patients. Most cases occurred in males with a median age of 47 (IQR, 37-59). Strongyloides/CMV co-infections occurred among immunocompromised hosts, especially in solid organ transplants and hematological or rheumatological diseases. Most of the patients underwent a course of steroid treatment before the diagnosis of co-infections. Other common immunomodulatory agents were tacrolimus and mycophenolate. The first clinical manifestations of co-infections were mainly gastrointestinal, followed by respiratory symptoms. CMV was, in most patients, co-infected with an isolated reactivation, although Strongyloides manifested especially as hyperinfection syndrome. Ganciclovir and ivermectin are the mainstays of CMV and Strongyloides treatment. However, the treatment mortality reported in this narrative review is around 52.4%. Interestingly secondary bacterial infections are common in CMV/Strongyloides-infected patients.

National survey of prevention and management of CMV infection in pediatric kidney transplantation in comparison to clinical practice guidelines.

Cytomegalovirus (CMV) is one of the most frequent opportunistic infections in kidney transplant (KT) recipients and is a risk factor for patient and graft survival after KT. Center-to-center variation, optimal prevention and treatment strategies in pediatric KT are currently unknown. This survey aimed to assess current CMV prevention and treatment strategies used among French pediatric KT centers. A web-based survey was sent to all 13 French pediatric kidney transplantation centers. Twelve (92%) centers responded to the survey. All centers used prophylaxis for the donor-positive/recipient-negative (D+/R-) group. For R + patients, 54% used prophylaxis, 37% used a pre-emptive strategy. In the low-risk group, D-/R-, 50% used a pre-emptive approach and 50% had no specific prevention strategy. The antiviral used by all centers for prophylaxis was valganciclovir (VGCV). The duration of prophylaxis varied from 3 to 7 months and the duration of viral load monitoring varied from 6 months to indefinitely. No center used a hybrid/sequential approach. For the treatment of CMV DNAemia, VGCV or intravenous GCV were used. Therapeutic drug monitoring of VGCV was performed in 5 centers (42%). Five centers reported drug resistance. Eight centers (67%) administered VGCV during the treatment of acute graft rejection. There is uniformity in CMV management in some areas among pediatric KT centers in France but not in others which remain diverse and are not up to date with current guidelines, suggesting unnecessary variation which could be reduced with better evidence to inform practice.

733. Letermovir treatment for refractory or resistant cytomegalovirus infection or disease with concurrent organ dysfunction: an interim analysis of a Phase 2 open label study.

Abstract Background Cytomegalovirus (CMV) disease is associated with increased morbidity and mortality following solid organ and hematopoietic cell transplantation. Currently, standard of care CMV treatments often have significant myelosuppressive or renal toxicities. Given letermovir’s favorable safety profile when used prophylactically, it may be a safe and efficacious alternative agent for CMV treatment. Methods A proof-of-concept, open-label trial was conducted in patients who lacked effective therapeutic options or presented with baseline organ dysfunction. Participants were eligible for enrollment if they were ≥12 years old and had documented CMV infection refractory to treatment defined as failure to achieve >1 log reduction in CMV viral load (VL) (when VL > 500 IU/mL) or lack of clinical improvement for CMV end-organ disease after ≥14 days of standard CMV treatment. Alternatively, patients with severe myelosuppression and renal dysfunction at baseline or genotypic antiviral resistance were also eligible. Participants were excluded if their current CMV infection developed while receiving letermovir for CMV prophylaxis. Letermovir was administered daily (480 mg PO/IV) for up to 12 weeks, with optional additional 12 weeks of treatment for secondary prophylaxis if clinically indicated. Results Ten patients met eligibility criteria and were enrolled. Reasons for enrollment included ganciclovir resistance (1/10), refractory CMV infection (6/10), renal dysfunction (7/10), and myelosuppression (7/10). The median baseline CMV VL was 1272 IU/ml [interquartile range (IQR); 925, 2546]. Six patients completed the study, three died due to complications of primary disease, and one discontinued due to diarrhea. Five patients (50%) had documented CMV viremia clearance, with a median time to first unquantifiable/undetectable CMV VL of 13 days [IQR; 9,18] and a median treatment duration of 53 days [IQR; 15,84]. Infections and GI disorders were the most common adverse events (AE), none considered related to study drug. No unexpected AE were observed during letermovir treatment. Conclusion Letermovir may be a safe and tolerable alternative for patients with treatment refractory CMV infection or for patients with severe baseline myelosuppression and renal dysfunction. Disclosures Matthew Cheng, MD, AstraZeneca: Honoraria|Cidara Therapeutics: Grant/Research Support|Scynexis Inc.: Grant/Research Support Sandra Burchett, MD, MSc, merck: Grant/Research Support Sarah P. Hammond, MD, F2G: Advisor/Consultant|F2G: Grant/Research Support|GSK: Grant/Research Support|Merck: Grant/Research Support|pfizer: Advisor/Consultant|Scynexis: Grant/Research Support Nicolas C. Issa, MD, AiCuris: Grant/Research Support|Merck: Grant/Research Support Francisco M. Marty, MD, SM, AlloVir: Advisor/Consultant|Amplyx: Advisor/Consultant|Amplyx: Grant/Research Support|Ansun: Grant/Research Support|Avir: Advisor/Consultant|Chimerix: Grant/Research Support|Cidara: Grant/Research Support|F2G: Advisor/Consultant|F2G: Grant/Research Support|Gilead: Grant/Research Support|Janssen: Advisor/Consultant|Kyorin: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Regeneron: Advisor/Consultant|Regeneron: Grant/Research Support|ReViral: Advisor/Consultant|Scynexis: Grant/Research Support|Symbio: Advisor/Consultant|Takeda: Grant/Research Support|United Medical: Advisor/Consultant|WHISCO: Grant/Research Support.

Real world experience: Examining outcomes using letermovir for CMV prophylaxis in high-risk allogeneic hematopoietic stem cell patients in the setting of using T-cell depletion as GVHD prophylaxis

BackgroundCytomegalovirus (CMV) infection significantly impacts the morbidity and mortality of patients undergoing allogeneic hematopoietic stem cell transplant (HSCT). Despite monitoring and pharmacologic prophylaxis with drugs such as valganciclovir or ganciclovir, rates of early CMV reactivation have continually persisted, contributing to increased rates of morbidity and mortality in allogeneic-HSCT patients. This study evaluates the outcomes of letermovir in preventing CMV reactivation and CMV-related complications in HSCT recipients with initiation of therapy at +21 days in high-risk patients. MethodsWe retrospectively analyzed adult patients at University of Southern California (USC) Norris Cancer Hospital who received allogeneic-HSCT from 2018 to 2020 with subsequent serial CMV monitoring and treatment. CMV reactivation was determined in patients if they had clinically significant serum CMV viremia (viremia requiring treatment) or organ involvement by day+100. Primary endpoint assessed was day+100 rates of CMV reactivation. Secondary end-points included 1-year OS, 1-year RFS, and incidence of GVHD. Descriptive statistics were used to compare characteristics between groups used in this study, with a significance level of α = 0.05. ResultsBetween 2018 and 2020, 116 adult HSCT recipients were reviewed. 51% were male and 49% were female; donor sources consisted of 27% match related donor (MRD) 28% match-unrelated donor (MUD), and 45% haploidentical donor. Of the 116 patients, 92 were identified as high-risk for CMV reactivation. 71 patients received letermovir prophylaxis, and 21 patients received no prophylaxis. In high-risk patients, after adjusting for GVHD status and transplant type, patients that received letermovir had no statistically significant difference of having D + 100 CMV reactivation compared to patients that did not receive letermovir. 1.02 (95% CI: 0.35, 3.20) (p = 0.97). Moreover, there were no statistically significant difference observed between letermovir treatment and 1-year OS, 1-year RFS, and incidence of GVHD. ConclusionPatients in the high-risk letermovir group had outcomes that were comparable to the lower risk “non-letermovir” group. There was no significant difference in CMV D + 100 reactivation between high-risk patients who did not receive letermovir compared to the patients who did. While other studies have shown that early initiation of letermovir may be associated with improved outcomes, our study shows that the use of letermovir with initiation at 21 days may not necessarily translate to improved secondary outcomes such as overall survival. Further prospective studies evaluating the time of initiating therapy and outcomes are needed.

Ocular Lesion Due To Congenital Infections with Cytomegalovirus, Toxoplasmosis: Diagnosis, Treatment And Follow-Up: A Prospective Study in Tehran, Iran

Intrauterine infections lead to involvement of various organs in fetus, including the eye. The aim of this study was to determine the frequency and clinical response of ocular lesions to specific drugs in infants with congenital Toxoplasma and cytomegalovirus infections. This historical cohort study was performed in the pediatric and ophthalmology department of Rasoul Akram Hospital in Tehran from October 2011 to November 2017. Patients included 78 infants with ocular involvement due to proven intrauterine infection (cataracts, glaucoma, and retinitis). Infants who did not undergo additional and diagnostic tests, eye examinations, and follow-up and did not receive effective treatment were excluded from the study. Three patients expired during the study. Finally, 37 patients (including 25 patients with cytomegalovirus and 12 patients with toxoplasmosis) were included to assess and the clinical response to ocular lesions was evaluated for one year. Of 12 cases with toxoplasmosis, 5 patients received complete treatment. Four patients had appropriate clinical responses. Of 25 patients with CMV, 18 patients received complete treatment and 9 patients had appropriate clinical responses. It concluded that successful treatment will be obtained in near 80% of ocular toxoplasmosis. So anti toxoplasma treatment is recommended in all confirmed congenital cases. About 50% of CMV infected cases (with hearing loss, ocular involvement) might respond well to antiviral therapy. We recommend anti CMV treatment in young congenital CMV (<2 years old) but it is not indicated in CMV infected cases with severe brain involvement.

Ocular lesion due to congenital infections (Cytomegalovirus, Toxoplasmosis), diagnosis, treatment and followup: A prospective study in Tehran, Iran

Background: Intrauterine infections lead to involvement of various organs in fetus, including the eye. The aim of this study was to determine the frequency and clinical response of ocular lesions to specific drugs in infants with congenital Toxoplasma and cytomegalovirus infections. Methods: This historical cohort study was performed in the pediatric and ophthalmology department of Hazrat Rasool Akram Hospital in Tehran from October 2011 to November 2017. Patients included 78 infants with intrauterine infection (proven) and ocular involvement (cataracts, glaucoma, and retinitis). Infants who did not undergo additional and diagnostic tests, eye examinations, follow-up and did not receive effective treatment were excluded from the study. Three patients expired during the study. Finally, 37 patients (including 25 patients with cytomegalovirus and 12 patients with toxoplasma) were included to assess and the clinical response to ocular lesions was evaluated for one year Results: Of 12 cases with toxoplasmosis, 5 patients received complete treatment and 4 patients had appropriate clinical responses. Of 25 patients with CMV, 18 patients received complete treatment and 9 patients had appropriate clinical responses. Conclusion: Successful treatment will be obtained in near 80% of ocular toxoplasmosis, so anti toxoplasma treatment is recommended in all confirmed cases. About 50% of CMV infected cases (with hearing loss, ocular involvement) might respond well to antiviral therapy, We recommend anti CMV treatment in any age ( <2 years old) but it is not indicated in CMV infected cases with severe brain involvement.

Risk Factors for CMV Viremia and Treatment-Associated Adverse Events Among Pediatric Hematopoietic Stem Cell Transplant Recipients.

BackgroundCytomegalovirus (CMV) causes substantial morbidity and mortality after hematopoietic stem cell transplantation (HSCT). There are limited data on risk factors for CMV viremia and the safety of antiviral medications used to treat CMV in children.MethodsWe conducted a single-center retrospective study of children who underwent HSCT between 2000 and 2016. We used log-logistic regression to evaluate associations between clinical characteristics and CMV-free survival at 100 days after HSCT. We compared the incidences of laboratory-defined adverse events (AEs) during treatment with ganciclovir and foscarnet.ResultsAmong 969 children, the median (interquartile range) age was 6.5 (3.1–11.5) years, and 80% underwent allogeneic HSCT. Two hundred forty-four (25%) children developed CMV viremia. Older age (odds ratio [OR], 0.95; 95% CI, 0.92–0.98), male sex (OR, 0.71; 95% CI, 0.51–0.99), non-Black, non-White race (OR, 0.56; 95% CI, 0.36–0.87), umbilical cord blood donor source (OR, 0.28; 95% CI, 0.08–0.97), and CMV seropositivity (R-/D+: OR, 0.17; 95% CI, 0.07–0.41; R+/D-: OR, 0.14; 95% CI, 0.09–0.21; R+/D+: OR, 0.08; 95% CI, 0.04–0.15) were associated with lower odds of 100-day CMV-free survival. Compared with foscarnet, ganciclovir was associated with lower incidences of thrombocytopenia (incidence rate ratio [IRR], 0.38; 95% CI, 0.15–0.97), electrolyte AEs (IRR, 0.42; 95% CI, 0.24–0.75), endocrine AEs (IRR, 0.52; 95% CI, 0.34–0.79), and renal AEs (IRR, 0.36; 95% CI, 0.19–0.65).ConclusionsCMV viremia occurred commonly among children after HSCT, and ganciclovir and foscarnet were associated with distinct toxicity profiles among children with CMV infection. These findings should be considered when developing CMV prevention and treatment strategies for children after HSCT.

Letermovir conversion after valganciclovir treatment in cytomegalovirus high‐risk abdominal solid organ transplant recipients may promote development of cytomegalovirus‐specific cell mediated immunity

To evaluate the association of conversion from valganciclovir to letermovir on cytomegalovirus-specific cellular immunity. Adult patients were included if they received a kidney or liver transplant between 8/1/2018-12/31/20, developed symptomatic, high-level CMV viremia and were converted to letermovir 480mg daily as monotherapy after treatment with ganciclovir-derivatives for a minimum of 4weeks and had subsequent CMV cell-mediated immunity (CMI) testing via ICS assay by flow cytometry (Viracor Eurofins T Cell Immunity Panel). Seven patients met inclusion criteria; 87.5% were male and recipients of a kidney transplant. All patients were CMV high risk (D+/R-). Mean time from transplant to CMV disease was 200±91 days. Peak viral load (VL) during CMV treatment was 540,341±391,211 IU/mL. Patients received a mean of 30±24weeks (range: 4-78weeks) of therapy with ganciclovir-derivatives at induction doses prior to letermovir introduction. The median absolute lymphocyte count (ALC) at letermovir initiation was 400/μL (IQR 575) and the median VL was 51.6 (range: ND-490) IU/mL. Most patients (n=5/7, 71.4%) experienced an increase in VL 1 and/or 2weeks after conversion to letermovir. All patients had positive CMI per ICS assay after conversion. Patients received a mean of 10.3±6.9weeks of letermovir prior to having a positive result. Median ALC at positivity was 900/μL. Immunosuppression was not further reduced from initiation of letermovir to demonstration of CMV CMI. No patient had progressive replication or breakthrough disease while maintained on letermovir and three patients (42.9%) underwent antiviral withdrawal without recurrence at the last follow-up. In this case series of abdominal transplant recipients with severe or persistent CMV infection, patients developed CMV-specific CMI after conversion to letermovir monotherapy. These data suggest that using letermovir in place of valganciclovir for secondary prophylaxis may address the lack of efficacy previously seen with this approach, as well as the issues that plague antiviral withdrawal with systematic monitoring. Future prospective studies are needed to evaluate this effect in a more controlled research environment with serial CMI testing to elucidate the optimal duration of letermovir when used in this way.

1190. Burden of Congenital Cytomegalovirus Among Newborns/Infants < 2 Years of Age From 2010 to 2020

Abstract Background Congenital cytomegalovirus (cCMV) is a leading cause of preventable congenital birth defects worldwide. In the United States, approximately 1 in 200 infants are born with cCMV and about 10% exhibit symptoms at birth; of those, 40-60% experience long-term sequelae including sensorineural hearing loss and developmental delays. As routine newborn surveillance is universally absent, it is difficult to assess the absolute burden of cCMV and demonstrate the need for CMV treatment and prevention. Here we describe the global epidemiologic burden of cCMV from 2010-2020 by performing a systematic review of the literature. Methods Publications from 2000-2020 on CMV-related epidemiologic, economic, and humanistic burden across all ages were identified using Medline, Embase, and LILACS. Epidemiologic burden estimates of cCMV in at-risk age groups (newborns [≤ 1 month] and infants [2 months to 2 years]) were extracted from recent studies published from 2010-2020, excluding previous systematic literature reviews, chart reviews, case series, gray literature, and studies in immunosuppressed populations. The primary outcome measure was seroprevalence, defined by CMV-specific immunoglobulin G titer or confirmed by CMV polymerase chain reaction in saliva or urinary samples. Results Of 8970 records on CMV epidemiologic burden across all ages, 3600 were screened (Fig. 1). Records were excluded based on study population, outcome, design, or other reason, yielding 157 articles; 24 reported cCMV infection in newborns/infants in 13 countries (Fig. 2). cCMV seroprevalence estimates differed based on type of screening (Fig. 3). cCMV seroprevalence ranged from 0.28-67.2% among publications reporting on universal screening (n=6), 0.6-29.2% among publications reporting on targeted screening (n=17) based on hearing loss, low birth weight, or small for gestational age, and 36.0% in one publication reporting on prenatal screening. Figure 1. Study selection for epidemiological burden cCMV, congenital cytomegalovirus Figure 2. Global map of the location and number of included studies Figure 3. cCMV seroprevalence and 95% confidence interval* by universal, targeted, and prenatal screening methods *Confidence intervals shown when available. cCMV, congenital cytomegalovirus Conclusion There is a worldwide lack of cCMV epidemiologic data with heterogeneity in seroprevalence, influenced by inconsistent and varied screening efforts. Implementation of consistent screening methods is essential to accurately describe the burden of cCMV, justify future vaccine (or other prevention or treatment) introduction, and measure impact. Disclosures Jacek Mucha, MS, Certara (Employee) Neumann Monika, Information Specialist, Certara (Employee) Witold Lewandowski, MD, BA, Certara (Other Financial or Material Support, Former employee during abstract development)Tata Consultancy Services (Employee) Magdalena Kaczanowska, MPH, Certara (Employee) Elvira Schmidt, MSc, Certara (Employee) Andrew Natenshon, MA, Moderna, Inc. (Employee) Carla Talarico, MPH, PhD, Moderna, Inc. (Employee) Philip Buck, MPH, PhD, Moderna, Inc. (Employee) John D. Diaz-Decaro, MS, PhD, Moderna, Inc. (Employee)

Letermovir Prophylaxis Versus Pre-Emptive Therapy for Cytomegalovirus after Hematopoietic Stem-Cell Transplantation

IntroductionCytomegalovirus (CMV) infection is one of the most common complication after allogeneic hematopoietic stem-cell transplantation (HSCT) still associated with significant morbidity and mortality. Although pre-emptive therapy (PET) are routinely used in treatment of CMV after SCT, their prophylactic use is limited by clinically unacceptable myelosuppression and nephrotoxicity. Letermovir, available since 2019 in Italy, is the first antiviral agent approved by FDA and EMA which is indicated for the prophylaxis of CMV infection in CMV seropositive (R+) patients undergoing SCT. Presently, cost and drug interactions are the main disadvantages of Letermovir use. We performed a single-center observational retrospective study to evaluate the efficacy of primary Letermovir prophylaxis for CMV infection among high-risk patients (R+) receiving HSCT from serological negative donor (D-).MethodsWe evaluated a cohort of R+/D- patients transplanted from January 2017 to December 2020 (86/235 transplanted patients): among those eligible for Letermovir prophylaxis (N=70), 29 patients (transplanted after 2019) received Letermovir until day +100, whereas 41 patients (the historical control group transplanted before 2019) received CMV PET only in case of increased viral load (CMV reactivation). Patients unable to take oral therapy at day +7 from HSCT or assuming drugs for concomitant clinical conditions bringing about major pharmacokinetic interaction were excluded (N=16). We compared day +100 and day +200 cumulative incidence of clinically significant CMV infection (CS-CMVi), defined according to drug registration trial: Letermovir discontinuation before day +100, CMV reactivation (CMV-DNAemia leading to PET), CMV tissue invasive disease, disease relapse and death from any causes. Survival functions between groups were estimated by the Kaplan-Meier method and compared using log-rank test. Moreover, the overall survival (OS), disease free survival (DFS), non-relapse mortality (NRM) and cumulative incidence of II-IV grade acute graft-versus-host disease (aGVHD) was compared in the two cohorts. Finally, we analyzed the number of accesses in day hospital from initial discharge to day +180, as an indirect cost-effectiveness evaluation of letermovir prophylaxis.ResultsNo severe adverse events related to the therapy were observed in the letermovir group. Letermovir prophylaxis started at a median of 11 days (range, 5-27) after HSCT. The median duration of Letermovir administration was 89 days (range, 40-113). The only early stop was due to patient death, not related to CMV or drug toxicity. CS-CMVi at day +100 occurred in 13.8% vs 61.0% in letermovir and historical group, respectively (p <0.001). Of note, none of the events in letermovir group was related to CMV reactivation whereas 24/25 in the historical group were. A trend toward lower CS-CMVi in the letermovir group was observed also at day +180 (44,8% vs 65,9%, p =0.080), with 6 late reactivations in patients who received prophylaxis. Moreover, at follow-up one patient in the experimental group and 3 in the control group developed CMV disease. Of note, in vivo T-cell depletion was used in 86% of patients in letermovir and 83% in historical group, and most of the CMV reactivations occurred after development of aGVHD: in 83% and 54% of patients, respectively. No differences in OS and DFS were observed between the two cohorts. Finally, a trend toward lower number of day hospital admissions was shown in patients who received letermovir prophylaxis (median 2 admissions, IQR 0-8, vs median 4.5, IQR 0-16), suggesting higher quality of life and costs reduction.ConclusionsOur real-life experience demonstrated the efficacy of Letermovir in reducing the incidence of CMV reactivation. Longer follow-up is needed to clarify advantages in terms of disease-free and overall survival. Further studies are needed to investigate the role of prophylaxis beyond day 100 in high risk patients, such as those who receive a T-depleted transplant or who develop aGVHD. The role of Letermovir prophylaxis on immuno-reconstitution and its cost-effectiveness remains to be evaluated. DisclosuresMarco: Jazz: Consultancy; Insight,: Consultancy; Janssen: Consultancy. Ferrero: EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Research Funding, Speakers Bureau; Morphosys: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Clinigen: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau.

S2649 Bacillus cereus Bacteremia in Alcoholic Cirrhosis

Introduction: Bacillus cereus (BC) is a gram positive, spore-forming environmental bacteria that can be found as transient normal human gastrointestinal (GI) flora. While BC is a common blood culture (BCx) contaminant, it can cause emetic or diarrheal foodborne illness via enterotoxin. This often resolves with supportive care. BC has been implicated in rare yet serious nosocomial and opportunistic infections in patients (pts) with hematological malignancies, intravenous drug use (IVDU), or indwelling devices. We present a case of non-GI BC infection in an alcoholic cirrhotic pt without traditional risk factors. Case Description/Methods: A 57-year-old female with diabetes (DM), alcohol use disorder, and alcoholic cirrhosis presented with malaise and worsening jaundice. Pt denied GI symptoms or fever. Pt received prednisone x 21 days for alcoholic hepatitis 2 weeks prior to admission and denied use since then. No history of IVDU. Pt was on spironolactone, thiamine, and folic acid. Physical exam showed stable vitals, intact mental status, non-distended and non-tender abdomen, and no cardiac murmur. MELD-Na on admission was 31 (Table 1). Toxicology screen, hepatitis A, B and C serology, EBV, and HIV were negative. Serum CMV PCR 27355 IU/mL. Multiple BCxs over 4 consecutive days were positive for BC. U/S abdomen was negative for hepatic lesions or ascites initially. Transesophageal echocardiogram was unremarkable. Pt was treated with IV vancomycin for 2 weeks. CMV treatment was deferred. Pt developed ascites during hospitalization without spontaneous bacterial peritonitis (SBP) and MELD-Na was 25 at discharge. Discussion: Cirrhotic pts are susceptible to infections due to associated immune dysfunction. Non-GI BC infections could be acquired exogenously via bacterial entry of disrupted skin or endogenously via ingestion of contaminated food. There are rare reports of BC bacteremia in cirrhotic pts causing SBP and necrotizing fasciitis. The pathogenesis was attributed to translocation of colonized Bacillus in the GI tract via increased intestinal permeability and hypoalbuminemia resulting in bacteremia or peritonitis due to impaired phagocytosis that failed to eradicate the infection. Our case demonstrated alcoholic cirrhosis with compounded immunocompromised status such as malnutrition, DM, steroid use, and CMV viremia could pose as a risk factor for non-GI BC infection and contribute to acute on chronic liver failure. Prompt recognition and treatment of BC infection is vital in cirrhotic pts to prevent fatality.Table 1.: Laboratory results on admission.

CMV viral load kinetics as surrogate endpoints after allogeneic transplantation.

BACKGROUNDViral load (VL) surrogate endpoints transformed development of HIV and hepatitis C therapeutics. Surrogate endpoints for CMV-related morbidity and mortality could advance development of antiviral treatments. Although observational data support using CMV VL as a trial endpoint, randomized controlled trials (RCTs) demonstrating direct associations between virological markers and clinical endpoints are lacking.METHODSWe performed CMV DNA PCR on frozen serum samples from the only placebo-controlled RCT of ganciclovir for early treatment of CMV after hematopoietic cell transplantation (HCT). We used established criteria to assess VL kinetics as surrogates for CMV disease or death by weeks 8, 24, and 48 after randomization and quantified antiviral effects captured by each marker. We used ensemble-based machine learning to assess the predictive ability of VL kinetics and performed this analysis on a ganciclovir prophylaxis RCT for validation.RESULTSVL suppression with ganciclovir reduced cumulative incidence of CMV disease and death for 20 years after HCT. Mean VL, peak VL, and change in VL during the first 5 weeks of treatment fulfilled the Prentice definition for surrogacy, capturing more than 95% of ganciclovir's effect, and yielded highly sensitive and specific predictions by week 48. In the prophylaxis trial, the viral shedding rate satisfied the Prentice definition for CMV disease by week 24.CONCLUSIONSOur results support using CMV VL kinetics as surrogates for CMV disease, provide a framework for developing CMV preventative and therapeutic agents, and support reductions in VL as the mechanism through which antivirals reduce CMV disease.FUNDINGMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

572. Antiviral Toxicities Among Pediatric Solid Organ Transplant Recipients

BackgroundGanciclovir (GCV) and valganciclovir (VGCV) are used for prophylaxis (PPX) and treatment for CMV in pediatric solid organ transplant (SOT) recipients, but the frequency and impact of toxicities from these medications are not well described.MethodsRetrospective cohort study of children undergoing SOT at Children’s Hospital of Philadelphia from Jan 2012 - Jun 2018. EMR were reviewed to identify laboratory-based toxicities between 15 days and 1 year post-transplant; medication management within 14 days of toxicity onset was recorded. Toxicities were defined as GCV or VGCV-associated if a patient was on the antiviral at toxicity onset. We defined acute kidney injury (AKI) as ≥50% change in creatinine (Cr) from 30 days prior, leukopenia as WBC < 3500/µL, neutropenia as ANC < 1000/µL, and thrombocytopenia as < 100K/µL. Incidence rates of toxicities on PPX and treatment were compared to rates during no antiviral using univariate Poisson regression.Results285 children received 299 SOTs: 108 liver, 91 kidney, 69 heart, 31 lung. Nearly half (46%) of toxicities during the first year after transplant occurred while on GCV or VGCV PPX or treatment, but their use accounted for only 23% of all follow-up time. Receipt of VGCV and GCV PPX and treatment were associated with significantly higher incidence rates of toxicities compared to no antiviral (Fig 1). Of 259 GCV or VGCV-associated toxicities, 44% (n=113) were leukopenia, 26% (66) neutropenia, 26% (66) AKI, and 6% (15) thrombocytopenia (Table 1). Most recipients of VGCV PPX (64%) sustained at least one toxicity while on PPX. AKI during VGCV PPX led to stopping/dose-adjusting of VGCV in 43% and of immunosuppression in 57% of cases. Neutropenia during VGCV PPX resulted in stopping/dose-adjusting of VGCV in 63%, of immunosuppression in 36%, and of TMPX/SMX PPX in 36% of cases. During VGCV PPX, 81% of AKI was stage II/III (≥100% change in Cr) and 65% of neutropenia was severe (< 500/µL); 11% of both AKI (n=6) and neutropenia (n=7) during VGCV PPX resulted in hospitalization.Figure 1. Incidence Rates of Toxicities from Day 15 through 1 Year After Transplant Table 1. Antiviral Use and Toxicity 2 Weeks to 1 Year After Transplant ConclusionGCV and VGCV use was associated with significant renal and hematological toxicities in pediatric SOT recipients. While VGCV and GCV are effective at preventing CMV disease in pediatric SOT, clinicians should consider risk of toxicity when evaluating CMV prevention strategies.DisclosuresKevin J. Downes, MD, Merck, Inc. (Grant/Research Support)