Preemptive Therapy For Cytomegalovirus Infection Research Articles

Antiviral medications for preventing cytomegalovirus disease in solid organ transplant recipients.

The risk of cytomegalovirus (CMV) infection in solid organ transplant recipients has resulted in the frequent use of prophylaxis to prevent the clinical syndrome associated with CMV infection. This is an update of a review first published in 2005 and updated in 2008 and 2013. To determine the benefits and harms of antiviral medications to prevent CMV disease and all-cause death in solid organ transplant recipients. We contacted the information specialist and searched the Cochrane Kidney and Transplant Register of Studies up to 5 February 2024 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. We included randomised controlled trials (RCTs) and quasi-RCTs comparing antiviral medications with placebo or no treatment, comparing different antiviral medications or different regimens of the same antiviral medications for CMV prophylaxis in recipients of any solid organ transplant. Studies examining pre-emptive therapy for CMV infection are studied in a separate review and were excluded from this review. Two authors independently assessed study eligibility, risk of bias and extracted data. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. This 2024 update found four new studies, bringing the total number of included studies to 41 (5054 participants). The risk of bias was high or unclear across most studies, with a low risk of bias for sequence generation (12), allocation concealment (12), blinding (11) and selective outcome reporting (9) in fewer studies. There is high-certainty evidence that prophylaxis with aciclovir, ganciclovir or valaciclovir compared with placebo or no treatment is more effective in preventing CMV disease (19 studies: RR 0.42, 95% CI 0.34 to 0.52), all-cause death (17 studies: RR 0.63, 95% CI 0.43 to 0.92), and CMV infection (17 studies: RR 0.61, 95% CI 0.48 to 0.77). There is moderate-certainty evidence that prophylaxis probably reduces death from CMV disease (7 studies: RR 0.26, 95% CI 0.08 to 0.78). Prophylaxis reduces the risk of herpes simplex and herpes zoster disease, bacterial and protozoal infections but probably makes little to no difference to fungal infection, acute rejection or graft loss. No apparent differences in adverse events with aciclovir, ganciclovir or valaciclovir compared with placebo or no treatment were found. There is high certainty evidence that ganciclovir, when compared with aciclovir, is more effective in preventing CMV disease (7 studies: RR 0.37, 95% CI 0.23 to 0.60). There may be little to no difference in any outcome between valganciclovir and IV ganciclovir compared with oral ganciclovir (low certainty evidence). The efficacy and adverse effects of valganciclovir or ganciclovir were probably no different to valaciclovir in three studies (moderate certainty evidence). There is moderate certainty evidence that extended duration prophylaxis probably reduces the risk of CMV disease compared with three months of therapy (2 studies: RR 0.20, 95% CI 0.12 to 0.35), with probably little to no difference in rates of adverse events. Low certainty evidence suggests that 450 mg/day valganciclovir compared with 900 mg/day valganciclovir results in little to no difference in all-cause death, CMV infection, acute rejection, and graft loss (no information on adverse events). Maribavir may increase CMV infection compared with ganciclovir (1 study: RR 1.34, 95% CI: 1.10 to 1.65; moderate certainty evidence); however, little to no difference between the two treatments were found for CMV disease, all-cause death, acute rejection, and adverse events at six months (low certainty evidence). Prophylaxis with antiviral medications reduces CMV disease and CMV-associated death, compared with placebo or no treatment, in solid organ transplant recipients. These data support the continued routine use of antiviral prophylaxis in CMV-positive recipients and CMV-negative recipients of CMV-positive organ transplants.

Population Pharmacokinetic and Pharmacodynamic Analysis of Valganciclovir for Optimizing Preemptive Therapy of Cytomegalovirus Infections in Kidney Transplant Recipients.

This study aimed to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model of valganciclovir for preemptive therapy of cytomegalovirus (CMV) infection in kidney transplant patients. A population PK/PD model was developed with Monolix. Ganciclovir concentrations and CMV viral loads were obtained retrospectively from kidney transplant patients receiving routine clinical care. Ten thousand Monte Carlo simulations were performed with the licensed dosages adjusted for renal function to assess the probability of attaining a viral load target of ≤290 and ≤137 IU/mL. Fifty-seven patients provided 343 ganciclovir concentrations and 328 CMV viral loads for PK/PD modeling. A one-compartment pharmacokinetic model coupled with an indirect viral turnover growth model with stimulation of viral degradation pharmacodynamic model was devised. Simulations showed that 1- and 2-log10 reduction of CMV viral load mostly occurred between a median of 5 to 6 and 12 to 16 days, respectively. The licensed dosages achieved a probability of reaching the viral load target ≥90% at days 35 to 49 and 42 to 56 for the thresholds of ≤290 and ≤137 IU/mL, respectively. Simulations indicate that in patients with an estimated glomerular filtration rate of 10 to 24 mL/min/1.73m2, a dose increase to 450 mg every 36 h may reduce time to optimal viral load target to days 42 and 49 from a previous time of 49 and 56 days for the thresholds of ≤290 and ≤137 IU/mL, respectively. Currently licensed dosages of valganciclovir for preemptive therapy of CMV infection may achieve a viral load reduction within the first 2 weeks, but treatment should continue for ≥35 days to ensure viral load suppression.

Letermovir for Prophylaxis and Pre-emptive Therapy of Cytomegalovirus Infection in Paediatric Allogeneic Haematopoietic Cell Transplant Patients.

Cytomegalovirus (CMV) infection is a frequent event in patients undergoing allogeneic haematopoietic cell transplantation (HCT) and is associated with increased morbidity and mortality due to eventual progress to end-organ disease. Letermovir prophylaxis for CMV infections has become a standard of care in adult HCT recipients due to its efficacy and high tolerability. However, itis not yet approved for paediatric patients. In a retrospective single-centre observational study we evaluated the use of letermovir for prophylaxis or pre-emptive treatment of cytomegalovirus (CMV) infection in seropositive paediatric HCT recipients receiving the compound outside of clinical trials. The primary endpoint was CMV reactivation requiring a change of medication. A total of 17 patients (seven female/ten male; median age 12.2 [range3.5-19] years, median body weight 39.5 [range15-63] kg; median follow-up time 463.7 [range41-1022] days) were identified who were started on oral (14) or intravenous (3) followed by oral (2) letermovir shortly after neutrophil engraftment at doses determined on the basis of age, weight, and concomitant cyclosporine use. Five patients had no evidence of viral replication (prophylactic use), while 12 patients had varying extents of viral replication (pre-emptive therapy). A change of therapy was required in one patient due to a sustained increase in CMV viral load, and in two patients, letermovir was stopped without later reactivation after initiation of palliative care for recurrent leukaemia. Of the 14 patients who completed treatment, 3 had evidence of transient viral replication after end of treatment that required no further antiviral treatment. No patients (of 17) discontinued letermovir dueto an adverse event. Letermovir was effective in controlling CMV infection in seropositive paediatric allogeneic HCT recipients and wasoverall well tolerated. Pending completion of the still ongoing paediatric investigation plans, letermovir will be an important adjunct to our options for control of infectious complications in this special population.

Fifteen-Year Surveillance of LTR Receiving Pre-Emptive Therapy for CMV Infection: Prevention of CMV Disease and Incidence of CLAD.

The efficacy of pre-emptive therapy in the prevention of cytomegalovirus (CMV) disease and the potential association of CMV infection with the occurrence of chronic lung allograft dysfunction (CLAD) was evaluated in 129 lung transplant recipients receiving pre-emptive therapy based on pp65-antigenemia or CMV-DNA in the blood and in the bronchoalveolar lavage. Seventy-one (55%) patients received pre-emptive ganciclovir/valganciclovir (GCV/VGCV) for CMV infection for a median of 28 (9-191) days. Possible CMV disease occurred in six (5%) patients and was healed after the GCV/VGCV therapy. The cumulative incidence of CLAD was 38% and 54% at 5 and 10 years. Acute rejection and CMV load in the blood (but not in the lung) were independent predictors of the occurrence of CLAD. Pre-emptive therapy is highly effective in preventing CMV disease in lung recipients and does not induce a superior incidence of CLAD compared to what reported for other cohorts of patients who received an extended antiviral prophylaxis.

Transition from antigenemia to quantitative nucleic acid amplification testing in cytomegalovirus-seropositive kidney transplant recipients receiving preemptive therapy for cytomegalovirus infection

Due to the high costs, the strategy to reduce the impact of cytomegalovirus (CMV) after kidney transplant (KT) involves preemptive treatment in low and middle-income countries. Thus, this retrospective cohort study compared the performance of antigenemia transitioned to quantitative nucleic acid amplification testing, RT-PCR, in CMV-seropositive KT recipients receiving preemptive treatment as a strategy to prevent CMV infection. Between 2016 and 2018, 363 patients were enrolled and received preemptive treatment based on antigenemia (n = 177) or RT-PCR (n = 186). The primary outcome was CMV disease. Secondarily, the CMV-related events were composed of CMV-infection and disease, which occurred first. There were no differences in 1-year cumulative incidence of CMV-disease (23.7% vs. 19.1%, p = 0.41), CMV-related events (50.8% vs. 44.1%, p = 0.20), neither in time to diagnosis (47.0 vs. 47.0 days) among patients conducted by antigenemia vs. RT-PCR, respectively. The length of CMV first treatment was longer with RT-PCR (20.0 vs. 27.5 days, p < 0.001), while the rate of retreatment was not different (14.7% vs. 11.8%, p = 0.48). In the Cox regression, acute rejection within 30 days was associated with an increased the risk (HR = 2.34; 95% CI = 1.12–4.89; p = 0.024), while each increase of 1 mL/min/1.73 m2 of 30-day eGFR was associated with a 2% reduction risk of CMV-disease (HR = 0.98; 95% CI = 0.97–0.99; p = 0.001). In conclusion, acute rejection and glomerular filtration rate are risk factors for CMV disease, showing comparable performance in the impact of CMV-related events between antigenemia and RT-PCR for preemptive treatment.

Decreased hospitalization and cost benefit of using valganciclovir as a pre-emptive therapy for cytomegalovirus infection in pediatric transplant recipients

Decreased hospitalization and cost benefit of using valganciclovir as a pre-emptive therapy for cytomegalovirus infection in pediatric transplant recipients

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

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

Usefulness of valacyclovir prophylaxis for cytomegalovirus infection after anti-thymocyte globulin as rejection therapy.

Background/AimsAnti-thymocyte globulin (ATG) treatment for acute T-cell mediated rejection (TCMR) can increase the risk of cytomegalovirus (CMV) infection. We aimed to evaluate the effect of valacyclovir prophylaxis against CMV infection after ATG administration as anti-rejection therapy.MethodsWe retrospectively analyzed 55 kidney transplant recipients (KTRs) receiving ATG for steroid resistant TCMR. In all KTRs, we used intravenous ganciclovir during ATG injection. In 34 KTRs treated before July 2013, we performed preemptive therapy for CMV infection after ATG therapy. They were regarded as the historic control group (CONT). After July 2013, we used valacyclovir maintenance for 1 month after ATG therapy in 21 patients (VAL). The primary outcome was the incidence of CMV infection, and the secondary outcomes were subsequent acute rejection, and graft and patient outcome.ResultsValacyclovir prophylaxis significantly reduced the incidence of CMV infection (VAL, 9.6% vs. CONT, 67.6%; p < 0.001), and CMV-free survival rate was higher in the VAL group compared to the CONT group (p = 0.009). In the VAL group, two cases of CMV infection were limited to CMV viremia, but CMV disease or syndrome (n = 3) was detected in the CONT group. There was no difference in graft failure (CONT, 70.5% vs. VAL, 47.6%; p = 0.152), incidence of subsequent rejection after ATG treatment (CONT, 41.1% vs. VAL, 33.3%; p = 0.776), and graft or patient survival between the two groups. There were no major adverse events associated with valacyclovir prophylaxis.ConclusionsIn conclusion, valacyclovir prophylaxis is effective in the prevention of CMV infection after ATG treatment for steroid resistant TCMR.

Randomized Controlled Trials to Define Viral Load Thresholds for Cytomegalovirus Pre-Emptive Therapy.

BackgroundTo help decide when to start and when to stop pre-emptive therapy for cytomegalovirus infection, we conducted two open-label randomized controlled trials in renal, liver and bone marrow transplant recipients in a single centre where pre-emptive therapy is indicated if viraemia exceeds 3000 genomes/ml (2520 IU/ml) of whole blood.MethodsPatients with two consecutive viraemia episodes each below 3000 genomes/ml were randomized to continue monitoring or to immediate treatment (Part A). A separate group of patients with viral load greater than 3000 genomes/ml was randomized to stop pre-emptive therapy when two consecutive levels less than 200 genomes/ml (168 IU/ml) or less than 3000 genomes/ml were obtained (Part B). For both parts, the primary endpoint was the occurrence of a separate episode of viraemia requiring treatment because it was greater than 3000 genomes/ml.ResultsIn Part A, the primary endpoint was not significantly different between the two arms; 18/32 (56%) in the monitor arm had viraemia greater than 3000 genomes/ml compared to 10/27 (37%) in the immediate treatment arm (p = 0.193). However, the time to developing an episode of viraemia greater than 3000 genomes/ml was significantly delayed among those randomized to immediate treatment (p = 0.022). In Part B, the primary endpoint was not significantly different between the two arms; 19/55 (35%) in the less than 200 genomes/ml arm subsequently had viraemia greater than 3000 genomes/ml compared to 23/51 (45%) among those randomized to stop treatment in the less than 3000 genomes/ml arm (p = 0.322). However, the duration of antiviral treatment was significantly shorter (p = 0.0012) in those randomized to stop treatment when viraemia was less than 3000 genomes/ml.DiscussionThe results illustrate that patients have continuing risks for CMV infection with limited time available for intervention. We see no need to alter current rules for stopping or starting pre-emptive therapy.

Comparison of Two Commercial Automated Nucleic Acid Extraction and Integrated Quantitation Real-Time PCR Platforms for the Detection of Cytomegalovirus in Plasma

Quantitation of cytomegalovirus (CMV) viral load in the transplant patients has become a standard practice for monitoring the response to antiviral therapy. The cut-off values of CMV viral load assays for preemptive therapy are different due to the various assay designs employed. To establish a sensitive and reliable diagnostic assay for preemptive therapy of CMV infection, two commercial automated platforms including m2000sp extraction system integrated the Abbott RealTime (m2000rt) and the Roche COBAS AmpliPrep for extraction integrated COBAS Taqman (CAP/CTM) were evaluated using WHO international CMV standards and 110 plasma specimens from transplant patients. The performance characteristics, correlation, and workflow of the two platforms were investigated. The Abbott RealTime assay correlated well with the Roche CAP/CTM assay (R2 = 0.9379, P<0.01). The Abbott RealTime assay exhibited higher sensitivity for the detection of CMV viral load, and viral load values measured with Abbott RealTime assay were on average 0.76 log10 IU/mL higher than those measured with the Roche CAP/CTM assay (P<0.0001). Workflow analysis on a small batch size at one time, using the Roche CAP/CTM platform had a shorter hands-on time than the Abbott RealTime platform. In conclusion, these two assays can provide reliable data for different purpose in a clinical virology laboratory setting.

Occurrence of adverse events caused by valganciclovir as pre-emptive therapy for cytomegalovirus infection after allogeneic stem cell transplantation is reduced by low-dose administration.

Pre-emptive therapy with valganciclovir (VGCV) has become the standard therapy for preventing cytomegalovirus (CMV) infection after allogeneic hematopoietic stem cell transplantation (HSCT). The effectiveness of low-dose VGCV (900 mg per day) has been shown to be equal to that of standard-dose VGCV (900 mg twice daily); however, individualized optimal dosing and toxicity of VGCV have not been reported. We conducted a retrospective study to evaluate the optimal dose of VGCV as pre-emptive therapy for preventing CMV infection by comparing the frequency of adverse events (AEs) and clinical efficacy in a low-dose VGCV group with those in a standard-dose VGCV group. Thirty-eight patients who were administered VGCV because of CMV antigenemia after HSCT were analyzed. Neutropenia (standard-dose group: 33%, low-dose group: 15%, P = 0.26) and thrombocytopenia (standard-dose group: 39%, low-dose group: 15%, P = 0.14) were frequent AEs of VGCV, and a significantly higher frequency of overall AEs was detected in the standard-dose group than in the low-dose group (P < 0.01). In comparison of dosage based on weight, dosage of VGCV >27 mg/kg was closely related to onset of AEs (P = 0.04). Low-dose VGCV was not inferior in clinical efficacy, including clearance rate of CMV antigenemia and incidence of consequent CMV disease, to standard-dose VGCV as was previously reported. Initial low-dose VGCV for pre-emptive CMV therapy markedly reduces hematologic toxicity and has clinical efficacy equivalent to that of standard-dose VGCV. It is therefore reasonable for patients, except for noticeably overweight patients, to be given initial low-dose VGCV.

Genetic mechanism associated with congenital cytomegalovirus infection and analysis of effects of the infection on pregnancy outcome.

We aimed to compare the diagnostic value of various detection methods for cytomegalovirus (CMV) infection, to investigate the genetic mechanism associated with CMV infection in pregnant women, and to analyze the risk of sequelae development in fetuses with CMV infection. A total of 300 participants who had the same immunosuppressive regimen and received preemptive therapy for CMV infection were prospectively enrolled in this study; they included 289 vaccine trial participants. The gB-absorbed CMV IgG assay was performed for each vaccine trial participant. The healthy women were divided into 2 groups, and amniotic fluids were collected from them at 15-18 weeks of gestation to test for CMV seropositivity before conception by using IgM specific antibodies, CMV-DNA, and IgG analysis. In 104 cases, cord blood sera and urine specimens were also collected from the infants and examined. The sensitivity and specificity of immediate-early messenger RNA and pp67 (late) messenger RNA detection by the nucleic acid sequence-based amplification technique was comparable to those of virus isolation and PCR. Furthermore, an association between single nucleotide polymorphisms in the TLR-2 gene and congenital CMV infection was observed and confirmed. Moreover, CMV infection during early pregnancy has been shown to have a much more severe effect on the pregnancy outcome compared to infection during later stages of pregnancy.

Oral Valganciclovir As Preemptive Therapy for Cytomegalovirus Infection in Allogeneic Hematopoietic Stem Cell Transplant Recipients

▪Introduction: Cytomegalovirus (CMV) infection remains one of the most important complications after allogeneic hematopoietic stem cell transplantation (AlloHSCT). Preemptive therapy with oral VGC or intravenous ganciclovir has replaced universal prophylaxis. We investigated the effect of oral VGC as preemptive therapy on CMV reactivation or infection in AlloHSCT.Patient & Methods: We retrospectively studied 30 consecutive adult recipients of HLA-identical sibling allogeneic peripheral blood stem cell transplant from June 2011 through June 2014 to analyze the safety and efficacy of preemptive therapy for the treatment of CMV infection. Among 30 patients we studied the results of 13 patients with CMV DNA positivity. All 13 recipients and their donors were seropositive for CMV Ig G status. Their diagnosis of pretransplantation were as 8 acute myeloid leukemia (61 %) and 5 acute lymphocytic leukemia (39 %). Median age was 39 years (range 21-54). There were 9 men and 4 women (Table-1). The patients received no prophylaxis against CMV. Blood/serum samples from all patients were routinely monitored for CMV-DNA using PCR twice weekly. We iniciated pre-emptive therapy for CMV as the viral load was above and equal to 500 copies/ml in two consecutive samples. VGC was given twice daily 900 mg for 2 weeks, and maintened at a dose daily 900 mg until viral load is undetectable.Results: The PCR test was persistently negative in 17 patients (57 %) and positive at least once in 13 (43%)patients. All patients with CMV reactivations were on immunsupressive treatment. CMV infection was cleared in most patients within 2 weeks, but for those with stable or increasing CMV levels, the induction period was continued. Twelve patients were treated with oral VGC on an outpatient basis and they all became CMV negative after the first week of treatment. Only one patient received intravenous ganciclovir and he was also CMV negative after the first week of treatment. While no positivity was identified in any of the patients who received VGC on day 21, clinically unimportant low titer CMV positivity was noted in three of these patients. VGC was continued at same dose and no positivity was detected after 2-3 weeks. We were obligated interrupt VGC in only four patients for serious side effects namely neutropenia and thrombocytopenia. We did not observe CMV-related mortality.Conclusions: We concluded that VGC therapy could be safely used at outpatient clinics, with frequent monitorization to prevent severe myelotoxicity. In conclusion, based on our findings, oral VGC is effective and safe in the pre-emptive treatment of CMV disease following allo-HSCT. Therefore, preemptive strategy by oral VGC appears preferable to the prevention of CMV disease in alloHSCT with its advantage of effectiveness and usage in outpatient clinic condition.Table- 1:Management and outcome of the patient characteristics with CMV-reactivationPatients with CMV reactivation/Total number of patient13/30Median age, years (range)39 (21-54)Gender Male Female9 4Diagnosis AML ALL8 5CMV serologic status Donor+/Recipient +13Preperative regimen Bu-Cy CY-TBI Flu/Amsc(FLAMSA)8 4 1GVHD propylaxis CSA+MTX CSA+MTX+MM12 1GVHD prior to CMV reactivation Acute chronic without GVHD7 1 5Prednisolone treatment at the time of starting VCG Yes No8 5IST at the time of starting VGC Yes No13 0Median duration of CMV reactivation (day)44 (8-330)Viral load before antivial treament (copies/ml)1153 (78-12800)Treatment VGC (900 mg, twice daily for induction) GC (5 mg/kg, twice daily for induction) VGC+GC9 (70 %) 1 (7 %) 3 (23 %)Total treatment duration (day)24 (10-51)CMV DNA at the end of the treatment Conversion to negative Persistently positive (low titer < 50 copies/ml)10 (77 %) 3 (23 %)Serious side effects Interruption of therapy due to neutropenia Interruption of therapy due to thrombocytopenia Reactivation3 (23 %) 1 (7 %) 2 (15 %)Abbreviations: AML: acute myeloid leukemia, ALL: acute lymphoblastic leukemia, CMV: cytomegalovirus,GVHD: graft-versus host disease, CSA: cylosporine, MTX: methotrexate, MMF: mycophenolate mofetil, PDN:prednizolone, IST: Immunosupressive treatment, VGC: valganciclovir, GC: ganciclovir, Bu: Busulfan, Cy: cylophosphamide, TBI: total body irradiation DisclosuresNo relevant conflicts of interest to declare.

Evaluation of Published Single-Nucleotide Polymorphisms (SNPs) Associated with Cytomegalovirus Infection and Disease after Hematopoietic Cell Transplantation in a Large Caucasian Cohort

▪Background: Cytomegalovirus (CMV) infection is one of the most common complications after hematopoietic cell transplantation (HCT). Regardless of preemptive therapy for CMV infection, CMV disease still occurs in approximately 10% of seropositive HCT recipients, resulting in high mortality. A number of studies have reported the association between CMV infection or disease and single-nucleotide polymorphisms (SNPs), however the results have not been validated in independent cohorts. We performed a candidate gene validation study of previously reported SNPs using a large genome-wide association study (GWAS) cohort.Patients and methods: This GWAS cohort included donor-recipient (D/R) pairs who received the first allogeneic transplantation between 1990 and 2011 at the FHCRC. Of an overall cohort of 4855 D/R pairs, 2193 Caucasian CMV seropositive recipients and their donors (seropositve or seronegative) were analyzed. Two CMV phenotypes were analyzed: any infection within 100 days (only among 1585 recipients transplanted after 1995, antigenemia-based preemptive therapy administered) and CMV disease within 1 year after HCT. Published SNPs associated with CMV infection or disease were collected by a PubMed search using the keywords 'cytomegalovirus’ and 'SNP’ or 'polymorphism.’ A p-value of less than 0.05 was required for validation. Genomic DNA samples from donors and recipients were analyzed using the Affymetrix GeneChip Genome-Wide Human SNP Array 5.0 (for one third of subjects) and Ilummina OmniExpress Beadchip Array (for the remainder). When the candidate SNPs were not included in the arrays, we imputed genotypes using IMPUTE software. Among genotyped and imputed SNPs, only SNPs with a minor allele frequency ≥0.05, call rate ≥90%, and Hardy-Weinberg equilibrium ≥0.0001 were analyzed. Donor serostatus, age, year of transplantation, donor type, HLA disparity, and intensity of conditioning regimen were used as adjustment factors as appropriate.Results: Among the 2193 HCT recipients in our cohort, 1009/1585 (64%) had CMV infection and 354/2193 (16%) had CMV disease. We identified 52 SNPs in 31 publications that reported significant associations between SNPs and CMV infection or disease (median number of subjects in these studies, 215; range, 37-1770). A total of 32 SNPs were available for the analysis. For CMV infection, six SNPs in four genes (TLR9, MCP1, CCR5, and CD209) in recipient or donor met our validation criteria (Table). For all SNPs but one, however, the direction of the association was opposite to that reported in the previous studies. We validated one SNP association (TLR9/rs5743836) in the recipient exactly as originally reported (adjusted HR, 1.16; 95% CI, 1.00-1.34, p=0.043). The donor genotype at this SNP was also significantly associated with CMV infection (adjusted HR, 1.47; 95% CI, 1.02-2.14, p=0.041) (Table), but an association with donor genotype was not assessed in the original publication. As for CMV disease, a different TLR9 SNP (rs352140) in donors was identified as significant (adjusted HR, 0.74; 95% CI, 1.02-2.14, p=0.029), although the ethnicity is different from the reported cohort (Table). None of the candidate SNPs in the recipient genome were associated with CMV disease.Conclusions: Of 32 SNPs that were previously reported to be associated with either CMV infection or disease, we were only able to validate two, both in TLR9. Most of the previously reported SNP associations for CMV infection or disease were not replicated in this large GWAS cohort. The inability to replicate these SNP associations does not necessarily negate the original discoveries, since many factors, including the sample size, could account for the different results. Our findings suggest that results of SNP association studies should be confirmed in multiple independent large cohorts and the biological mechanisms underlying the associations should be examined before clinical application. Unbiased discovery approaches are needed to determine the genetic associations of CMV infection and disease. [Display omitted] DisclosuresBoeckh:Chimerix Inc.: Consultancy, Research Funding; Viropharma Inc.: Research Funding; Genentech/Roche: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Clinigen: Consultancy.

Clinical study of cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation

This study was purposed to investigate the cytomegalovirus (CMV) infection and its related factors after allogenic hematopoietic stem cell transplantation (allo-HSCT). A total of 108 patients who received allo-HSCT in zhongda hospital from January 1, 2004 to March 31, 2014 were enrolled in this study. The CMV infection rate and the median time when the CMV-DNA was positive for the first time, and the risk factors related with CMV infection, CMV disease distribution and mortality after allo-HSCT were analyzed. The results showed that the infection rate of CMV was 52.78% (57/108), the median time of CMV infection was 44 d, especially during 30 d-100 d after transplantation. The univariate analysis showed that CMV infection rate was related with the HLA-identical situation between the donor and the recipient, and whether the use of anti-human thymus globulin(ATG) in conditioning regimen, neutropenic period after transplantation exceeded 10 d and graft-versus-host disease (GVHD). Multivariate analysis showed that CMV infection rate was related with neutropenic period longer than 10 d after transplantation and graft-versus-host disease (GVHD). The mortality of the patients with CMV disease was 58.82% (10/17), in which the mortality of CMV interstitial pneumonia was highest. The CMV infection was one of the most commonly happened infection after allo-HSCT. It is concluded that to reduce the incidence of CMV disease and mortality, the best choice of allo-HSCT is HLA-identical donor, ATG should be used during the conditioning process, and neutropenic period should be reduced less than 10 days. Moreover, it is necessary to strengthen the preemptive therapy of CMV infection actively.

The Occurrence of Cytomegalovirus Gastrointestinal Disease in Patients with Gastrointestinal Graft-Versus-Host Disease and Its Related Clinical Outcomes in the Era of Preemptive Therapy for Cytomegalovirus Infection

Abstract 492Diagnosis and therapeutic decision of gastrointestinal (GI)-graft-versus-host disease (GVHD) mainly rely upon clinical symptoms and exclusion of other causes of GI dysfunction. Particularly, the presence of CMV-GI-disease should be examined with immunostaining of biopsy. However, there have been few reports about the occurrence of CMV-GI-disease in patients with GI-GVHD in the era of preemptive therapy for CMV infection with real-time quantitative polymerase chain reaction (RQ-PCR) and its related outcomes.Between January 2008 to December 2010, 392 adult patients with AML, ALL, MDS, and CML underwent allogeneic stem cell transplantation (SCT) and all had serial monitoring for CMV DNA based on RQ-PCR followed by initiation of preemptive therapy. Ninety-seven percent of recipients and 84% of donors were CMV-seropositive before SCT. Clinical GI-GVHD based on symptoms, stool studies, and endoscopic findings developed in 114 patients (29%) and they were treated by high-dose systemic steroid. Of these patients, 103 patients performed endoscopic biopsies not only at the time of onset of clinical symptoms but also during the clinical course of GI-GVHD in the absence of response to steroid, and all samples from biopsies were immunohistochemically stained. The median age of the 103 patients was 40 years (range, 15–70). These patients consisted of AML (n=59), ALL (n=29), MDS (n=12), and CML (n=3) transplanted from sibling (n=45), unrelated (n=48), familial-mismatched donors (n=8), and umbilical cord donors (n=2). Conditioning regimens consisted of myeloablative (76%) and reduced-intensity regimens (24%). Anti-thymocyte globulin was given as a part of conditioning in 41 patients (40%). GVHD prophylaxis was based on administering calcineurin inhibitor with short-course methotrexate. GI-GVHD was developed as a manifestation of not only acute GVHD (aGVHD, 87%) but also overlap syndrome (13%). Isolated GI-GVHD was 30%. Eighty-nine patients (86%) initially presented with GI-GVHD, whereas 14 patients (14%) developed GI-GVHD after the treatment of GVHD of other organs.Of the 103 patients, 60 (58%) had histologic findings for GI-GVHD (lower gut, n=41, 40%; lower gut + upper gut, n=10, 10%; upper gut, n=9, 8%) and 26 (25%) had positive immunohistochemical stain for CMV-GI-disease (lower gut, n=13, 13%; lower gut + upper gut, n=4, 4%; upper gut, n=9, 8%). The CMV-GI-disease developed at a median time of 56 days after SCT (range, 20–403). Multivariate analyses revealed that older age over 30 years (RR 4.42, 95%CI 1.10–17.84), HLA-mismatched donors (RR 3.41, 95%CI 1.21–9.60), and higher grade of GVHD (grade III+IV aGVHD or severe cGVHD, RR 3.24, 95% CI 1.22–8.60) were significant risk factors for CMV-GI-disease. Most patients (73%) developed CMV-GI-disease after the treatment of GI-GVHD or other organs of GVHD, whereas CMV-GI-disease developed concurrently with GI-GVHD in other 27%. After the anti-viral therapy with ganciclovir or foscarnet, 14 patients (54%) showed complete resolution of CMV-GI-disease, while 12 patients (46%) failed to show any response.There were 4 patterns of development of pathologically proven GI-GVHD and CMV-GI-disease (Figure). GVHD-specific survival of patients with CMV-GI-disease was significantly lower than patients without CMV-GI-disease (36.2% vs. 79.3%, P = 0.002). Patients with both GI-GVHD and CMV-GI-disease (n=18) had significantly inferior GVHD-specific survival than other 3 patterns of development of GI-GVHD and CMV-GI-disease (24.5% vs. 78.2%, P = 0.001).Our data demonstrate 25 percent of patients with clinical GI-GVHD developed CMV-GI-disease during the treatment or at the time of diagnosis of GI-GVHD even in the era of preemptive therapy for CMV disease based on RQ-PCR, especially in older patients, HAL-mismatched transplants, and higher grade of GVHD. Patients with CMV-GI-disease, especially who concurrently had pathologically proven GVHD, had inferior GVHD-specific survival. Thus, we reemphasize the need of endoscopic biopsy with immunohistochemical stain for CMV disease if ever possible at the diagnosis of GI-GVHD as well as in the absence of response to treatment of GVHD, especially in high risk groups, which can facilitate proper selection of treatment. Additionally, novel prophylactic measures such as immunotherapy and drug prophylaxis should be considered in this specific group of patients. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

A Universal Preemptive Therapy for Cytomegalovirus Infections in Children After Live-Donor Liver Transplantation

Cytomegalovirus (CMV) infection remains the most common and critical viral infection that occurs after liver transplantation (LT). The current set of guidelines recommends prophylaxis over a preemptive therapy for pediatric LT; however, the data regarding the optimal approach after LT in children are limited. We conducted a universal preemptive therapy for CMV infection in 113 children (median: 16 months) after live-donor LT at the largest pediatric LT center in Japan between November 2005 and August 2009. CMV-pp65 antigenemia was monitored weekly regardless of the subjects' CMV serostatus after LT, and ganciclovir therapy was initiated when CMV-pp65 antigenemia was positive. The overall success rate of LT was 91.7%. CMV-pp65 antigenemia became positive in 37 (33%) recipients, and the positivity with their CMV serostatus was as follows: donor (D)+/recipient (R)-: 62%, D+/R+: 36%, D-/R+: 11%, and D-/R-: 8%. Among the D+/R- (n=29) and D+/R+ (n=44) recipients, 38% (n=11) and 64% (n=28) recipients were able to avoid the use of ganciclovir, respectively. Human CMV disease was documented in six (5%) recipients, and they were successfully treated with ganciclovir without any sequelae. A universal preemptive therapy for CMV infection after live-donor LT was successful for reducing the use of antiviral agents and for controlling CMV infection and disease in children.

Valganciclovir as Pre-Emptive Therapy for Cytomegalovirus Infection in Allogeneic Haematopoietic Stem Cell Transplant Recipients

In haematopoietic stem cell transplant (HSCT) recipients, cytomegalovirus (CMV) infection contributes significantly to morbidity and mortality in both the early and late post-transplant period. Ganciclovir (GCV) is the treatment of choice for CMV, but requires intravenous administration, a fact that complicates its long-term use. Oral valganciclovir (VGCV) and intravenous GCV were recently shown to have similar efficacy for pre-emptive CMV treatment in solid organ transplant recipients, but relatively limited data are available in HSCT recipients. The objectives of this study were to compare the efficacy of VGCV versus intravenous GCV or foscarnet (FOS) for pre-emptive therapy of active CMV infection in allogeneic HSCT and to determine the incidence of adverse effects and relapses. This was a 2-year prospective, comparative cohort study in which 237 episodes of pre-emptive therapy for active CMV infection were collected in 166 allogeneic HSCT recipients out of 717 included in the Spanish Network for Research on Infection in Transplantation (RESITRA/REIPI) database. Intravenous GCV was the first-line treatment in 112 episodes, intravenous FOS in 38 episodes, and oral VGCV in 87 episodes. VGCV was used as pre-emptive therapy for active CMV infection in 87 episodes. Excluding episodes considered as relapse, VGCV was as successful (91.4% [74/81]) as GCV (83.7% [87/14]) or FOS (75.8% [25/33]). In the VGCV arm, 7 (8.6%) cases were considered treatment failures: 4 (4.9%) because of adverse events, 1 (1.2%) due to persistent viral activity and 2 (2.5%) based on clinical decision. There were also 6 (7.4%) cases of recurrent infection. No statistically significant differences were found when compared to GCV or FOS. In allogeneic HSCT recipients, VGCV seemed effective and safe in the pre-emptive therapy of active CMV infection.

Leukopenia in Kidney Transplant Patients With the Association of Valganciclovir and Mycophenolate Mofetil

Cytomegalovirus (CMV) is the most common viral infection after transplantation. Valganciclovir (VGC) is established for prophylaxis and treatment of CMV infections, but leukopenia which appears in 10% to 13% (severe in 4.9%) is the principal side effect. We have recently noted an increased incidence of leukopenia and severe neutropenia among our renal transplant patients and thought to identify the associated factors. We conducted a retrospective analysis of all kidney transplantations performed between January 2005 and December 2006. All patients received mycophenolate mofetil (MMF), tacrolimus, and steroids. VGC was used for targeted prophylaxis and preemptive therapy of CMV infection, with doses adjusted to renal function. Of the 64 patients undergoing renal transplantation 13 (20.3%) developed leukopenia within 3 ± 2 months after transplantation with severe neutropenia in 5 (7.8%). All patients were on MMF and VGC (VGC 605 ± 296 mg/d). Leukopenia was significantly associated with simultaneous liver–kidney transplantation and with second kidney transplantations ( P < .01). The incidence of leukopenia was higher among patients under VGC since day 1 of transplantation ( P = .008) with maximal incidence observed among patients prescribed 900 mg/d as opposed to those on lower doses ( P < .01). There was no increase in CMV infection among patients with a low dose of VGC. No patient developed clinical CMV disease. In conclusion, VGC prophylaxis was associated with an increased frequency of leukopenia on MMF–tacrolimus treated patients or regimens. Low-dose VGC for CMV prophylaxis appeared to be as effective as high-dose treatment, and associated less frequently with leukopenia and neutropenia.

Validation of a DNAemia cutoff for preemptive therapy of cytomegalovirus infection in adult hematopoietic stem cell transplant recipients

A randomized trial comparing a DNAemia cutoff of 10 000 copies per ml whole blood and first pp65 antigenemia positivity for initiation of preemptive therapy of human cytomegalovirus (HCMV) infection in adult hematopoietic stem cell transplant recipients was completed. DNAemia was chosen for cutoff definition since it is more automatable and standardizable than antigenemia, and more closely reflects the actual viral replication. The primary end point of the study was to compare the number of patients treated in the two arms. A total of 83 patients (42 in the DNAemia, and 41 in the antigenemia arm) were enrolled in the study. The incidence of HCMV infection, as detected by the relevant randomization assay (76% in the DNAemia versus 85% in the antigenemia arm), was comparable in the two arms, whereas the number of patients treated was significantly lower in the DNAemia arm (63 versus 80%, P=0.02). A single patient in the DNAemia arm suffered from biopsy-proven HCMV gastric disease diagnosed in the absence of detectable virus in blood. The incidence of graft-versus-host disease, and transplantation-related mortality did not differ between the two arms. In conclusion, our study shows that the use of a cutoff significantly reduces the number of patients requiring antiviral treatment, thus sparing unnecessary drug administration.