Risk Of Cytomegalovirus Viremia Research Articles

Predictors of cytomegalovirus reactivation after allogeneic hematopoietic cell transplantation: Insights from a real-world experience

BackgroundWe aimed to investigate factors associated with cytomegalovirus (CMV) viremia and CMV disease and its impact on post-transplant outcomes including overall survival (OS) following allogeneic hematopoietic stem cell transplantation (Allo-SCT). MethodsWe conducted a single-center retrospective study including 452 Allo-SCT recipients (matched unrelated donor, MUD 61%; haploidentical, haplo 39%) from 2016 to 2021. Data were analyzed using SPSS v28. Descriptive (chi-square and t-test), Kaplan-Meier and regression analyses were conducted. ResultsThe median age was 57 years. Sixty-one percent were males and 84.3% were Caucasians. CMV serostatus was positive in 59.1% of recipients. The median follow-up was 24.4 months. CMV viremia and CMV disease were observed in 181 (40%) and 32 (7%) patients, respectively. Among CMV seropositive recipients, 65% developed CMV viremia and 11% were noted to have CMV disease compared to 4% and 1% in seronegative recipients, respectively (p < 0.001). Patients with CMV disease had significantly lower OS than those without CMV disease (median 14.1 months vs. not reached, p = 0.024); however, OS was not associated with CMV viremia (median not reached in both groups, p = 0.640). Letermovir prophylaxis was used in 66% (n = 176/267) of CMV seropositive recipients, but no impact was observed on the incidence of CMV viremia or CMV disease and OS. ConclusionsCMV disease leads to significantly inferior survival after an allogeneic hematopoietic cell transplantation. Recipient CMV seropositive status was associated with the risk of CMV viremia and CMV disease, and this was not abrogated with the use of Letermovir prophylaxis.

#45 Antibiotic Exposure and Risk of Cytomegalovirus Viremia Among Pediatric Hematopoietic Stem Cell Transplant Recipients at a Single Institution

Abstract Background Cytomegalovirus (CMV) causes substantial morbidity and mortality after hematopoietic stem cell transplantation (HCT), and antibiotic exposure after HCT is increasingly recognized as a risk for negative clinical outcomes. Recent studies identified an association between receipt of antibiotics with an anaerobic spectrum of activity and infection with cytomegalovirus (CMV) after HCT in adults. We sought to evaluate the association between anaerobic antibiotic exposure and CMV viremia in a well-characterized cohort of pediatric HCT recipients. Method We conducted a single-center retrospective cohort study of HCT recipients &amp;lt;18 years of age who underwent HCT at Duke University between 2000 and 2016. Routine pre-emptive surveillance testing for CMV was performed; CMV viremia was defined as a positive whole blood hybrid capture CMV DNA assay or quantitative plasma CMV PCR. We used log-logistic regression to evaluate associations between anaerobic antibiotic exposure (vancomycin, metronidazole, meropenem, piperacillin-tazobactam) and CMV viremia-free survival at 100 days after HCT. The first model considered anaerobic antibiotic exposure in the first 14 days after HCT as a binary variable. The second model considered anaerobic antibiotic exposure in the first 100 days as a time-varying variable; once a subject was exposed to a specific antibiotic, they were considered exposed for the remainder of the study period. Both models adjusted for year of HCT, age, race, HCT type and donor cell source, underlying diagnosis, conditioning regimen, CMV serostatus, and treatment for graft-versus-host-disease. Results Among 966 children, median (interquartile range) age was 6.5 (3.1, 11.5) years. Hematologic malignancy was the indication for transplantation in 417 (43%) subjects. Of 770 allogeneic HCT, 566 (74%) were from an umbilical cord blood donor and 204 (26%) were from a bone marrow donor. The majority of HCT were recipient CMV-seronegative and donor CMV-seronegative (R-/D-; 537, 56%), with 24 (2%) R-/D+, 270 (28%) R+/D-, and 135 (14%) R+/D+ transplants. Within the first 100 days after HCT, 692 (72%) children received vancomycin, 363 (38%) received metronidazole, 231 (24%) received meropenem, and 121 (13%) received piperacillin-tazobactam. Exposure to vancomycin (OR=0.86; 95% CI: 0.59, 1.26), metronidazole (OR=0.76; 95% CI: 0.53, 1.10), meropenem (OR=1.19; 95% CI: 0.74, 1.90), or piperacillin-tazobactam (OR=1.03; 95% CI: 0.55, 1.92) in the first 14 days after HCT was not associated with the risk of CMV viremia-free survival at 100 days. Similarly, we found no increased risk of CMV viremia with anaerobic antibiotic exposure in the first 100 days after HCT (vancomycin OR=0.90; 95% CI: 0.60, 1.34; metronidazole OR=0.80; 95% CI: 0.53, 1.21; meropenem OR=0.98; 95% CI: 0.60, 1.62; piperacillin-tazobactam OR=0.69; 95% CI: 0.38, 1.23). Conclusion In this study of pediatric HCT recipients, we did not find evidence of an association between anaerobic antibiotic exposures and CMV viremia risk. However, future pediatric and adult studies are warranted to evaluate this previously reported association in other populations, including studies evaluating for a possible role of the gut microbiome in modifying CMV viremia risk after HCT.

923. Respiratory Syncytial and Parainfluenza Virus Infection Increase the Risk of Cytomegalovirus Reactivation in Allogeneic Hematopoietic Cell Transplant Recipients

BackgroundRespiratory virus infections are associated with significant and specific local and systemic inflammatory response patterns, which may lead to reactivation of latent viruses. We examined whether viral upper (URTI) or lower respiratory tract infection (LRTI) with common respiratory viruses increased the risk of CMV viremia after allogeneic hematopoietic cell transplantation (HCT). MethodsWe retrospectively analyzed patients undergoing allogeneic HCT between 4/2008 and 9/2018. CMV surveillance was performed weekly and the presence of upper and lower respiratory symptoms were evaluated by multiplex respiratory viral PCR. We used Cox proportional hazards models to evaluate risk factors for development of any CMV viremia or high level CMV viremia in the first 100 days post-HCT. Each respiratory virus infection episode was considered positive for 30 days beginning the day of diagnosis.ResultsAmong 2,545 patients (404 children, 2141 adults), 1,221 and 247 developed CMV viremia and high level CMV viremia, respectively, in the first 100 days post-HCT. Infections due to human rhinoviruses (HRV, N=476) were most frequent, followed by parainfluenza viruses 1-4 (PIV, N=139), seasonal human coronaviruses (COV, N=134), respiratory syncytial virus (RSV, N=77), influenza A/B (FLU, N=35), human metapneumovirus (MPV, N=37), and adenovirus (ADV, N=61). In adjusted models, RSV LRTI was associated with increased risk of developing CMV viremia at all levels (Figures 1 and 2), and PIV or RSV URTI increased the risk of high level CMV viremia; all other viruses showed no association in univariable models. Figure 1. Model estimates for associations between LRTI and development of any CMV viremia Figure 2. Model estimates for associations between LRTI and development of high level CMV viremiaConclusionWe demonstrated that RSV and PIV infections are associated with an increased risk for development of CMV viremia after allogeneic HCT. This novel association provides the rationale to explore virus-specific inflammatory pathways that may trigger CMV reactivation. CMV viremia may also serve as an endpoint in clinical trials that assess new preventative or therapeutic interventions of RSV or PIV infection. Disclosures Alpana Waghmare, MD, Allovir (Scientific Research Study Investigator)Ansun Biopharma (Scientific Research Study Investigator)Kyorin Pharmaceutical (Advisor or Review Panel member) Janet A. Englund, MD, AstraZeneca (Consultant, Grant/Research Support)GlaxoSmithKline (Research Grant or Support)Meissa Vaccines (Consultant)Pfizer (Research Grant or Support)Sanofi Pasteur (Consultant)Teva Pharmaceuticals (Consultant) Michael Boeckh, MD PhD, AlloVir (Consultant)Ansun Biopharma (Grant/Research Support)Astellas (Grant/Research Support)EvrysBio (Consultant, Other Financial or Material Support, Options to acquire equity, but have not exercised them)Gilead Sciences (Consultant, Grant/Research Support)GlaxoSmithKline (Consultant)Helocyte (Consultant, Other Financial or Material Support, Options to acquire equity, but have not exercised them)Janssen (Grant/Research Support)Kyorin (Consultant)Merck (Consultant, Grant/Research Support)Moderna (Consultant)Symbio (Consultant)Takeda (formerly known as Shire) (Consultant, Grant/Research Support)VirBio (Consultant, Grant/Research Support)

NUDT15 polymorphism influences the metabolism and therapeutic effects of acyclovir and ganciclovir

Nucleobase and nucleoside analogs (NNA) are widely used as anti-viral and anti-cancer agents, and NNA phosphorylation is essential for the activity of this class of drugs. Recently, diphosphatase NUDT15 was linked to thiopurine metabolism with NUDT15 polymorphism associated with drug toxicity in patients. Profiling NNA drugs, we identify acyclovir (ACV) and ganciclovir (GCV) as two new NNAs metabolized by NUDT15. NUDT15 hydrolyzes ACV and GCV triphosphate metabolites, reducing their effects against cytomegalovirus (CMV) in vitro. Loss of NUDT15 potentiates cytotoxicity of ACV and GCV in host cells. In hematopoietic stem cell transplant patients, the risk of CMV viremia following ACV prophylaxis is associated with NUDT15 genotype (P = 0.015). Donor NUDT15 deficiency is linked to graft failure in patients receiving CMV-seropositive stem cells (P = 0.047). In conclusion, NUDT15 is an important metabolizing enzyme for ACV and GCV, and NUDT15 variation contributes to inter-patient variability in their therapeutic effects.

The safety and effctiveness of donor memory T lymphocyte infusions after hematopoietic stem cell transplantation with ab T cell depletion platform in children with acute leukemia

T-cell ab depletion prevents “graft-versus-host” disease (GVHD), does not impair engraftment, and improves the outcomes of hematopoietic stem cell transplantation (HSCT) from a haploidentical donor. Memory T lymphocyte infusions (CD45RA-depleted) can transfer functional immunity to common pathogens to recipients. In a randomized study, we explored the safety and effctiveness of donor memory T lymphocyte infusions (DLI) in children with leukemia after HSCT with ab T cell depletion platform. The study was approved by the Independent Ethics Committee and the Scientifi Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Ministry of Healthcare of the Russian Federation. A total of 149 patients were enrolled in the study; 76 patients were randomly assigned to the DLI group and 73 patients were allocated to the control group. Donors were haploidentical related in 91% of cases. The myeloablative conditioning regimen included treosulfan and total body irradiation. Anti-thymocyte globulin (ATG) was excluded from the conditioning regimen, instead, we used a combination of abatacept and tocilizumab. Graft processing involved TCRab-/CD19-depletion. The main parameters of assessment included the cumulative risk of detection of cytomegalovirus (CMV) DNA and the cumulative risk of grade II–IV GVHD. The additional parameters of assessment were the cumulative risk of transplant-related mortality, the cumulative risk of relapse, the overall and event-free survival rates, and the parameters of immune recovery. A historical control group was used to compare the primary outcomes of HSCT with ATG and an alternative immunomodulatory regimen (abatacept and tocilizumab). The cumulative risk of grade II–IV GVHD was 14% in the experimental group and 12% in the control group (p = 0.8). The cumulative risk of CMV viremia was 45% and 55% in the experimental and control groups, respectively (p = 0.4). In the prospective cohort, the rates of transplant-related mortality, the cumulative risk of relapse, and the overall survival were 2%, 25%, and 80%, respectively, without statistical diffrence between the arms. In the experimental group, we noticed a tendency toward an increase in the proportion of patients who developed an immune response to CMV in the early post-HSCT period. The substitution of ATG with tocilizumab and abatacept was not accompanied by a higher incidence of GVHD or graft failure; it was associated with signifiantly lower transplant-related mortality rates (2% vs 13%, p = 0.002) and improved immune recovery in the early post-HSCT period. Prophylactic infusions of donor memory lymphocytes are safe and may be used for further improvement in. the results of HSCT with ab T cell depletion platform.

Efficacy of 3 Months vs. 6 Months of Valganciclovir Prophylaxis for Heart Transplant Recipients at Intermediate Risk (R+) for CMV Complications

<h3>Purpose</h3> Heart Transplant recipients previously exposed to CMV infection are considered intermediate risk for post-transplant CMV complications. Many centers therefore utilize "universal" prophylaxis for 3-6 months to mitigate this risk. However, it remains unclear how long prophylaxis should be continued post-transplant in this population. In the present analysis, we compared post-transplant CMV outcomes in patients receiving 3 vs. 6 months of valganciclovir prophylaxis in a multicenter, retrospective analysis. <h3>Methods</h3> Retrospective analysis of 321 intermediate risk (CMV R+) HTx recipients from 6 U.S. centers between 2010-2018 treated with universal prophylaxis with valganciclovir for either 3 months (n = 277) or 6 months (n = 44). The primary endpoint was the development of CMV viremia or end-organ disease resulting in the escalation of anti-CMV therapy. The secondary endpoint was hospitalization for CMV-related infection. <h3>Results</h3> Of the 321 patients in the analysis, 13.4% (n = 43) developed CMV viremia or end-organ infection requiring escalation of anti-CMV therapy, and 3.4% (n = 11) were hospitalized for CMV infection. Overall, there was no significant difference in the primary endpoint in patients treated with 3 months of valganciclovir compared to 6 months (12.6% vs. 18.2%, p = 0.316; Figure 1A). There was a trend toward reduction in CMV hospitalization in the 6-month treatment group (Figure 1B), but this did not achieve statistical significance (3.6% vs. 2.3%, p = 0.651), potentially due to a low number of events. <h3>Conclusion</h3> We found no difference in the risk of CMV viremia or hospitalization for CMV using either a 3-month or 6-month regimen for prophylaxis in HTx recipients at intermediate risk for CMV (R+).

Prevalence and correlates of plasma cytomegalovirus viremia among newly reported HIV/AIDS patients in Taizhou city, 2017-2018

Objective: To study the prevalence and correlates of plasma cytomegalovirus (CMV) viremia among newly reported antiretroviral therapy (ART)-naive HIV/AIDS patients in Taizhou during 2017-2018. Methods: CMV DNA was measured in plasma specimens of newly reported ART-naive HIV/AIDS patients by quantitative PCR. Both univariable and multivariable logistic regression analyses were carried out to evaluate CMV viremia correlations among the individuals. Results: Of 612 HIV/AIDS patients, 480 (78.4%) were male, 125 (20.4%) were over 60 years old, 177 (28.9%) were infected via homosexual transmission, and 430 (70.3%) via heterosexual transmission. The prevalence of CMV viremia among HIV/AIDS patients was 13.4% (82/612). Multivariable logistic regression analysis showed that the risk of CMV viremia in CD4+ lymphocyte cells counts (CD4+) ≤200 cells/μl group was higher than CD4 counts >500 cells/μl (OR=5.10, 95%CI:1.74-14.96, P=0.003); The median CMV DNA level (log10) of 82 viremic patients was 1.57 (P25,P75:1.04,2.13); Viremic patients with CD4 counts ≤200 cells/μl had the highest CMV viral load (P<0.01). Conclusions: Among ART-naive HIV/AIDS patients, the prevalence of CMV viremia was significantly associated with immunodeficiency status. Further research is needed to evaluate the association between CMV viremia and the course of HIV infection.

Significance of Cytomegalovirus Specific T Lymphocytes in Kidney Transplant Recipients

Introduction CMV viremia is routinely used to confirmed CMV infection after kidney transplantation. Also, immune assays can be applied to predict viremia development or guiding prophylaxis and preemptive therapies. Most of the immunological assays rely on functional methods that detect INFγ after stimulation of lymphocytes with viral peptides. There is also MHC multimers assay that identifies antigen-specific lymphocytes crucial for controlling virus latency. It was proved for allogeneic stem cell transplant recipients that levels 2 to 10 cells/μl can successfully protect against CMV infection. Unfortunately, it is not for kidney transplant recipients. We hypothesize that CD28 expression may serve as an additional functional marker for viral-specific lymphocytes, as CD28 occurs with CMV infection and it is linked with early, intermediate and late antigen-specific T lymphocytes differentiation status. Thus, the aim of these study was to verify whether the CMV specific T lymphocytes or extended phenotype of CMV specific T lymphocytes may be used as a marker of CMV viremia in kidney transplant recipients. Materials and Methods CMV viremia was monitored in 52 kidney transplant recipients every three months, in two-years lasting follow-up. CMV specific lymphocytes were measured as CD8+ lymphocytes using MHC multimer assay. Further, CMV specific lymphocytes were assessed for CD28 expression (Figure 1).Values were reported both as percentages as well as absolute cell count. Results and Discussion CMV specific CD8+ T cells, expressing CD28 were superior for identification of patients at risk of viremia development after kidney transplantation. A cut-off value below 3 cells/μl successfully predict CMV viremia with acceptable specificity and sensitivity confirmed by ROC analysis, AUC values 0,774 – 0,951 depends on time posttransplant (Figure 2).The overall risk of CMV viremia was strongly associated with donor/recipient (D/R) serological status before transplantation, analyzed with Kaplan-Meier survival analysis (Figure 3).The highest risk of viremia development was associated with CMV primary infection (D+/R-). Interestingly, CMV positive recipients transplanted from CMV positive donor (D+/R+) had a higher risk of viremia when compared to uninfected donors (D-/R+), despite increased levels of CMV specific T lymphocytes (Figure 4).Conclusion Collectively, CMV specific T lymphocytes testing enables personalized assessment of recipient’s immune system. This data may be used for CMV viremia risk stratification, that could be applied for tailored pharmacotherapy after kidney transplantation. National Centre for Research and Development, Poland (No. STRATEGMED1/233368/1/NCBR/2014). National Science Centre, Poland (No. NN402420738 and NN402562440).

25 Pre-emptive therapy for cmv viremia in living donor liver transplant recipients: a single centre experience

Background CMV infection is among the most common complication after liver transplantation which may result in graft loss, survival and increased cost. There are two major strategies for CMV disease prevention after transplantation: preemptive therapy and universal prophylaxis. We present our cohort of recipients of Living Donor Liver Transplant (LDLT) with non-detectable CMV DNA pre-transplant, with moderate risk of CMV viremia (D+/R+, d-/R+), who were preemptively treated. Aim To determine whether preemptive strategy may be feasible approach in patients with moderate risk for CMV viremia in LDLT and its appropriateness for Acute Cellular Rejection(ACR), length of hospital stay and risk of developing other infection and all-cause mortality. Method In this retrospective cohort, 225 adults with moderate risk for CMV viremia who underwent LDLT at Shifa International Hospital from 29/4/2011 to 26/4/2016 were included. All recipients were checked for CMV viremia at day 7, patients with significant viremia (DNA >137 IU/ml) were treated for CMV preemptively. Non-viremic patients on day 7 were only re-checked if had deranged LFT on follow up. Results Out of 225 patients, 83 (36.8%) patients had detectable CMV DNA at day 7. Patients with higher pre-transplant MELD >18 had more chances of developing CMV viremia n=42 (50.6) than those with MELD Conclusions Pre-emptive CMV strategy may be an acceptable approach in patients with moderate risk of CMV viremia in resource constraint setting; however, this needs prospective randomised trials for validation.

CMV Viremia and African-American Ethnicity Are Risk Factors for Post-Engraftment Blood Stream Infections in Pediatric Allogeneic Blood and Marrow Transplantation

Background: Blood stream infections (BSI) are a major source of morbidity and mortality after allogeneic blood and marrow transplantation (BMT). In studies of risk for BSI various factors have been identified. The impact of cytomegalovirus (CMV) viremia, however, on risk has not been assessed. This is important since both CMV infection and ganciclovir (GCV), the mainstay of pre-emptive therapy, have myelosuppressive and immunosuppressive effects. We conducted a retrospective analysis to test the hypothesis that CMV viremia predisposes allogeneic BMT patients to BSI.Methods: We retrospectively analyzed 278 allogeneic BMTs performed at Children's Healthcare of Atlanta between January 1st 2005 and December 31st 2014 that met eligibility criteria. The primary outcome was the first episode of BSI occurring between day +30 and +100 seen in engrafted patients following allogeneic BMT. We compared clinical characteristics between patients with and without BSI. This analysis was based on a time dependent competing risk model. Risk events including acute GVHD and CMV viremia were counted only when they preceded the BSI. We performed a multivariate analysis to estimate the effect of CMV viremia on risk for BSI in the post-engraftment period (days +30-100).Results: The median age was 9 years (range 0-22 years). 44.6% of the patients were Caucasian, while 38.5% were African-American. 59.7% received an unrelated marrow, unrelated cord or the alternative donor transplant. 60.8% were transplanted for a hematologic malignancy. The cumulative incidence of BSI between day +30 and+100 was 21.9% (95% confidence interval (CI), 17.5-27.3%). The median day of BSI development was 54 (range 30-99). The leading cause of BSI was Staphylococcus epidermidis. Gram-positive cocci were responsible for 71.4% of all BSIs. In the multivariate analysis, three factors were significant: grade III/IV aGVHD (hazard ratio (HR)=3.490, 95% CI 1.530-7.980, P=0.003), CMV viremia (HR=3.410, 95% CI 1.410-8.250, P=0.007), and African-American ethnicity (HR=2.520, 95% CI 1.130-5.600, P=0.024). Form of insurance (Medicaid/no insurance vs. other), employed as a surrogate for income level, had no influence on risk. In the 57 patients with CMV viremia, the frequency of neutropenia (<500/mm3) after the development of CMV viremia until day +100 was 26.3% (15/57), significantly higher than that observed in patients without CMV viremia (5.4% (12/221), P<0.001).Conclusion:Our analysis of risk for post-engraftment BSI in children yielded three factors. One, aGVHD, is well established. The other two, CMV viremia and African-American ethnicity, have not been previously recognized. That CMV viremia would predispose to subsequent BSI is highly plausible. Our results suggest that the risk of CMV viremia may be mediated in part by neutropenia stemming from CMV or its treatment with ganciclovir. That African-American ethnicity has not previously been recognized as a risk factor may simply reflect the ethnic make up of previous studies. Our findings are consistent with those of studies performed in other settings, showing patients of African descent to be at increased risk for bacteremia and sepsis. An increased risk for BSI among patients of African descent could partly explain the concerning excess risk for transplant related mortality previously observed among these patients. DisclosuresNo relevant conflicts of interest to declare.

A Risk Score to Predict CMV Viremia within the First 100 Days after Allogeneic Stem Cell Transplantation Based on Pre-Transplant Parameters

▪Introduction:Cytomegalovirus (CMV) is a major infectious complication following allogeneic hematopoietic stem cell transplantation (HSCT). Risk of CMV infection varies between patients and individualized strategies for monitoring and therapy for CMV are needed. In this study, we attempted to establish a clinical score based on patient and transplant characteristics in order to predict the probability for early CMV viremia (CMV-V) within the first 100 days after HSCT.Methods:A total of 548 patients were evaluated after receiving HSCT between 2005 and 2012 at Princess Margaret Cancer Centre. CMV sero-negative recipients with CMV sero-negative donors (R-D-) were excluded. CMV-V was diagnosed in peripheral blood samples obtained on two occasions either by PCR (>200 IU/ml) or antigenemia testing (>2 positive cells/100000). A total of 378 patients were included into the study. Uni- and multivariable analyses were performed to identify risk factors for CMV-V. A weighted score was assigned to each factor based on the odds ratios determined by the multivariable analysis. A total score was calculated for each patient and used for assignment into one of 4 risk categories, the low risk (score 0-1), the intermediate (score 2-3), the high (score 4-5) and the very high (score 6-8).Median age for all patients was 51 years (range 17-71) and 173 (46%) were female. Matched related donors were used for two hundred fifteen patients (57%). Two hundred forty-three patients (64%) were transplanted for myeloid and 108 (29%) for lymphoid malignancies. One hundred thirteen patients (30%) were CMV sero-positive with a negative donor (R+D-) while 191 (51%) were recipient and donor CMV sero-positivity (R+D+). Graft versus host disease (GVHD) prophylaxis included CSA/MMF (n=200, 52%), and CSA/MTX (n=178, 48%). Myeloablative conditioning regimens were administered to 220 patients (58%), 158 patients (42%) were treated with a reduced intensity regimen. Three hundred-thirty seven patients (89%) received peripheral blood stem cells as a stem cell source. In vivo T cell depletion (TCD) with alemtuzumab was used in 138 (37%).Results: CMV-V occurred in 246 (64%) patients by day 100 post HSCT. The impact of patient and HSCT characteristics on the risk of CMV-V was assessed by multivariable analysis. The significant factors were CMV sero-status R+D- and R+D+, TCD, GVHD prophylaxis with MMF administration of myeloablative preparative regimens (Table 1). [Display omitted] CMV-V rates on the 4 new risk categories amounted to 93% in the very high-risk, 78% in high-risk, 41% in intermediate-risk and 11% in low-risk group (Fig 1). The risk score was also predictive for the occurrence of multiple CMV-V reactivations with rates of 71%, 45%, 19% and 4% for the very high, high, intermediate and low-risk groups, respectively.The overall survival (OS) rate at 2 years was 33%(n=56) in the very high-risk group compared to 50% in other-risk groups (n=147) (P=0.01) (Fig 2). Non-relapse mortality (NRM) was 53% in the very high-risk versus 33% in other-risk groups (P<0.001). However, there was no difference on cumulative incidence of relapse between the groups (P=0.3).The cumulative incidence of grades 1-4 acute GVHD, grades 2-4, grades 3-4 at day 120 and overall chronic GVHD at 2 years was 68%, 47%, 25% and 39% in very high-risk group versus 65%, 52%, 21% and 52% in other-risk groups, suggesting slightly lower incidence of chronic GVHD in very high-risk vs other-risk groups.Conclusion: We present a new clinical scoring system to stratify the risk of early CMV viremia after allogeneic HSCT based on patients and HSCT characteristics. Identifying the risk for each patient would facilitate decision making with respect to strategies including CMV prophylaxis, pre-emptive treatment or inclusion into clinical trials, as well directing the CMV monitoring policy post-transplant. In addition, the risk score was associated with higher risk of overall mortality and NRM in the very high-risk versus other-risk groups. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Single-Institution Randomized Prospective Trial of Pre-Emptive Therapy with Oral Valganciclovir Compared with IV Ganciclovir for Cytomegalovirus Infection after Allogeneic Hematopoietic Stem Cell Transplant (aHSCT), Delayed until Viral Load (VL) >10,000 Copies/Ml or >5,000 Copies/Ml X 2

Background: CMV remains a major cause of morbidity and mortality after aHSCT. The current standard of care for pre-emptive treatment of CMV viremia is IV ganciclovir (GCV). Oral valganciclovir (VGV) has been shown to be effective for the treatment of CMV retinitis in patients with HIV, and offers the advantage of oral administration. This prospective randomized clinical trial was designed to compare VGV to GCV as pre-emptive therapy for CMV viremia in the post-aHSCT population.Methods: Pts undergoing aHSCT at risk for CMV viremia, determined by donor and/or recipient CMV positivity, were monitored post-aHSCT by weekly quantitative whole-blood PCR. Due to concerns about oral absorption, pts with Grade III/IV gut GVHD were excluded. Positivity was determined by a VL >10,000 copies/mL or >5,000 copies/mL X 2. Pts were randomized to receive either: GCV 5mg/kg BID for 7 days followed by daily GCV 5mg/kg for 7 days or VGV 900mg BID for 7 days followed by 900mg daily for 7 days. At 14 days, PCR was reassessed. Pts with VL <5000 copies/mL completed a 21 day course of daily GCV or VGV. Pts with VL >5000 copies/mL but < initial value completed a 28 course of daily GCV or VGV. Pts with VL > initial value returned to BID GCV or VGV to complete a 28 day course (pts with 21 day level > day 14 level were removed from the study). Primary endpoint was clearance of viremia (VL <5000 copies/mL) within 28 days of initiation of therapy.Results: 37 pts were enrolled and 19 pts received treatment with VGV while 18 pts received treatment with GCV. Patient characteristics were as follows: median age was 53 (range 18–64); 25 males, 12 females; 25 pts had myeloablative conditioning regimens, 12 had non-myeloablative conditioning; 28 pts had unrelated donors, 9 had matched sibling donors; 32 pts received peripheral blood stem-cell products, 5 received bone marrow stem-cell products. These baseline characteristics were equally distributed across the two arms.Results: VGV and GCV showed equivalent efficacy as pre-emptive therapy (Table below). Toxicities were similar between the two arms: there were 35 grade III/IV events in the VGV arm and 42 grade III/IV events in the GCV arm. There were 20 grade III/IV hematologic toxicities in the VGV arm with 2 grade III episodes of neutropenia and 1 grade III febrile neutropenia. In the GCV arm, there were 23 grade III/IV hematologic toxicities, with 3 grade III episodes of neutropenia and 2 febrile neutropenic events. There were 2 deaths not related to the study medications or CMV. No patients developed CMV disease.Conclusions: In this trial VGV was equivalent to GCV with regard to clearance of viremia at 28 days. VGV can be considered an alternative pre-emptive therapy for CMV viremia post-aHSCT in patients without evidence of grade III/IV GVHD of the gut.RESULTSTOTALVGVGCVp-valueMedian Time to viremia (days)38 (16–98)35 (20–56)42 (16–98)0.046Median Time to initiation of Tx (days)45 (27–100)43 (27–80)49 (29–100)0.062Median VL at d0 (copies/mL)26191 (8964–244895)44264 (8964–239400)22948 (10480–244895)0.35Median VL at d14 (copies/mL)5249 (0–497820)5469 (0–345124)2562 (0–497820)0.83Viremia cleared at day 1415/37 (40.5%)7/19 (36.8%)8/18 (44.4%)0.74Viremia cleared at day 2128/37 (75.7%)14/19 (73.7%)14/18 (77.8%)1Viremia cleared at day 2832/37 (86.5%)17/19 (89.5%)15/18 (83.3%)0.66Recurrent viremia9450.71Median Time to recurrence (days)35 (15–54)39.5 (30–42)28 (15–54)0.39

Etiology and impact of cytomegalovirus disease on solid organ transplant recipients

The characteristics, etiology, natural history, and direct and indirect effects of CMV disease in solid organ transplant recipients are described. CMV is a common herpesvirus that may be present in the donor or recipient of a solid organ transplant. Even though it is rarely pathogenic in healthy patients, transplant recipients are at risk for CMV viremia and symptomatic disease due to their immune-suppressed status. In addition to symptoms directly attributed to active disease, CMV can have a variety of indirect effects. Indirect effects may include additional infectious complications, posttransplant lymphoproliferative disease, allograft rejection, allograft loss, or death. The three most prevalent risk factors for CMV infection are CMV seronegativity in a recipient of an organ from a CMV-seropositive donor, the type of organ transplanted, and the degree of immune suppression. CMV prophylaxis is effective at preventing disease, but may result in a delayed onset where CMV disease occurs once the prophylaxis is stopped. Knowledge of risk factors for CMV infection and disease, the natural history in transplant recipients, and its direct and indirect effects will help clinicians make appropriate decisions regarding the use of preventive strategies.