Received Valganciclovir Prophylaxis Research Articles

Cytomegalovirus Antiviral Resistance Among Kidney Transplant Recipients in a Phase 3 Trial of Letermovir vs Valganciclovir Prophylaxis

Abstract Background In a phase 3 trial, letermovir was noninferior to valganciclovir for cytomegalovirus (CMV) disease prophylaxis in kidney transplant recipients who were CMV-seronegative and received kidneys from donors who were CMV-seropositive. Genotypic antiviral resistance and CMV glycoprotein B (gB) genotype are reported. Methods Plasma samples with detectable CMV DNA were sequenced for the presence of known letermovir and valganciclovir resistance-associated amino acid substitutions (RASs) encoded by CMV gene regions (UL51, UL54, UL56, UL89, UL97) and prevalence of gB (UL55) genotypes (gB1–gB5). Results Among participants, 84 of 292 (letermovir) and 93 of 297 (valganciclovir) had evaluable data for ≥1 gene target. Letermovir RASs were not detected in participants who received letermovir prophylaxis; however, 3 had valganciclovir RASs (pUL97). Twelve participants who received valganciclovir prophylaxis had valganciclovir RASs (pUL54, pUL97), and 1 who did not receive letermovir during the trial had letermovir RASs (pUL56). All but 1 participant responded to valganciclovir treatment irrespective of breakthrough CMV DNAemia or frequency of RASs. gB1 was the most frequent genotype across all participants and subgroups. Conclusions Letermovir RASs were not detected with letermovir prophylaxis, supporting a low risk for development of resistance in kidney transplant recipients who were CMV-seronegative and received kidneys from donors who were CMV-seropositive. Clinical Trials Registration ClinicalTrials.gov, NCT03443869; EudraCT, 2017-001055-30.

Cytomegalovirus infection in heart transplant recipients: Epidemiology, risk factors, and long-term outcomes from a major transplant center in the United States

BackgroundDespite the use of antiviral prophylaxis, cytomegalovirus (CMV) remains a common opportunistic infection following heart transplantation. This study analyzes the rates, risk factors, and outcomes of CMV among heart transplant recipients. MethodsA retrospective cohort study was conducted of adults who underwent heart transplantation between January 1, 2011, and March 31, 2019. The primary outcome was clinically significant CMV infection (csCMVi), defined as CMV disease or asymptomatic infection requiring preemptive therapy. The secondary outcome was all-cause mortality. Patients received valganciclovir prophylaxis up to 6 months, depending on CMV donor/recipient serostatus. Kaplan-Meier curve and multivariable Cox regression were used for outcome analysis. ResultsAmong 553 heart transplant recipients, 101 (18.3%) experienced csCMVi, including 35 (6.3%) with CMV disease. csCMVi was uncommon during prophylaxis. In multivariable analysis, CMV D+/R- status (HR 12.88, 95% CI 6.76-24.56; p<0.001) and lower absolute lymphocyte counts in seropositive recipients (HR 1.48, 95% CI 1.23-1.79; p<0.001), but not CMV D+/R- patients (HR 1.18, 95% CI 0.94-1.47; p=0.162), were significantly associated with csCMVi. Sixty patients died during follow-up, and csCMVi was associated with increased mortality (HR 2.84, 95% CI 1.62-4.98; p<0.001). ConclusionsIn this large cohort of heart transplant recipients, csCMVi was linked to higher mortality. CMV D+/R- serostatus was associated with an increased risk of csCMVi, with lower absolute lymphocyte counts increasing risk only in CMV seropositive recipients. Strategies for optimizing CMV prevention in serodiscordant heart recipients are warranted.

Clinical utility of a cytomegalovirus-specific T cell assay in assessing the risk of post-prophylaxis cytomegalovirus infection and post-treatment relapse.

Cytomegalovirus (CMV) causes significant morbidity in solid organ transplant recipients (SOTR). Measuring cell-mediated immunity (CMI) may inform the risk of CMV infection after antiviral prophylaxis and predict relapse after CMV treatment. We serially assessed CMV CMI using the QuantiFERON-CMV assay (QF-CMV; Qiagen, Germantown, MD) in two cohorts of SOTRs: during valganciclovir prophylaxis and during treatment of CMV viremia. Results of CMI were correlated with post-prophylaxis CMV infection and post-treatment relapse, respectively. Only one (4.2%) of 24 CMV D+/R- patients demonstrated positive QF-CMV by the end of valganciclovir prophylaxis. Four (16.6%) patients developed post-prophylaxis CMV infection; all four had undetectable QF-CMV at end of prophylaxis. Among 20 patients treated for CMV infection, 18 (90%) developed QF-CMV levels>.2 IU/mL by end of antiviral treatment and none developed CMV relapse. In contrast, the single patient who relapsed after completing treatment had a CMV CMI<.2 IU/ml (p=.0036). Since CMV D+/R- SOTRs are unlikely to develop adequate CMV CMI while receiving valganciclovir prophylaxis, the utility of CMV CMI monitoring for risk stratification during time of prophylaxis had limited value. Conversely, CMV CMI testing may be a useful marker of the risk of CMV relapse after antiviral treatment.

#6846 CHRONIC CMV DIARRHOEA IN RENAL TRANPLANT RECIPIENTS - AN UNDERRECOGNISED SPECTRUM OF COMPARTMENTALISED GUT INVASIVE CMV DISEASE

Abstract Background and Aims Chronic diarrhoea in post-renal transplant recipients due to Cytomegalovirus (CMV) presents as Blood CMV PCR (polymerised chain reaction) positive chronic diarrhoea and Gut-invasive (rectal tissue PCR positive, blood PCR-negative) compartmentalised CMV. The available literature on compartmentalised gut CMV is scarce. The aim is to study the clinical presentation and outcome of patients with compartmentalized gut invasive CMV when compared with Blood CMV positive chronic diarrhea in renal transplant recipients. Method This is a retrospective single-centre follow-up study of patients with CMV disease who were transplanted between 2000 and 2020. Diagnostic variables like blood CMV PCR (polymerised chain reaction) positivity with constitutional symptoms, presence or absence of chronic diarrhoea, tissue PCR positivity and site of tissue biopsy were given harmony codes and 6 syndromes were identified – CMV diarrhoea (Blood PCR positive, presence of diarrhoea), compartmentalized gut invasive CMV (Blood PCR negative, presence of diarrhoea, rectal tissue quantitative CMV PCR positive), Acute CMV syndrome, CMV Esophagitis, CMV nephropathy, CMV cystitis. Out of which patients presenting with diarrhoea (first two groups) were included for analysis. The baseline descriptive statistical measures were carried out using analysis of variance. The time to CMV disease from transplant was computed by identifying the pattern of distribution at 10%, 50% and 90% between groups using reliability models. The time to death from diagnosis was analyzed by identifying the pattern by parametric log-logistic distribution. Survival analysis was done by a parametric reliability model identifying location, scale and threshold parameters, from which month-wise prediction of probabilities was found for survival. The proportion of adverse outcomes (relapse, death and graft loss) between the two groups were analyzed by one-way ANOVA and Tukey pairwise comparison. All the patients were followed up till death or last follow-up. Results Out of 2208 renal transplants done between 2000 and 2020, 118 (5.3%), patients developed CMV disease. Chronic diarrhoea was the presentation in 88 (57%), of which 47 had manifestations of CMV diarrhoea, and 41 had compartmentalized gut CMV. Induction agents used (CMV diarrhoea Vs compartmentalized gut CMV) were basiliximab (51% Vs 56%), ATG (27% Vs 17%), Grafalon (0% Vs,2.4%) and no induction (21%,24%). Only 31.9% and 26.8% received Valganciclovir prophylaxis for pre-specified indications respectively. The time to CMV diagnosis from transplant for 10%, 50% and 90% of patients (in months) was 12,63,154 for CMV diarrhoea;12,52 and 139 months for compartmentalized gut CMV. The mean duration (weeks) of diarrhoea was similar in both groups (7 Vs 7.3). Associated opportunistic infections causing diarrhoea were higher in compartmentalized gut CMV (28% Vs 46% p = 0.08); the commonest being cryptosporidium. Quantitative PCR in the blood ranged from 1245 to 2511345 copies/ml; whereas in gut tissue, it ranged from 1325 to 3517920/25 mg. The major histopathological finding in compartmentalized gut CMV was active inflammatory pathology in 34 (83%) patients. The probability of survival was significantly lower (72.6%; CI 60% to 83%) in CMV diarrhoea when compared with compartmentalized Gut CMV (87.2%; CI 76% to 94%) for initial 12 months (p&amp;lt;0.05); however at 5 years (56.2%, Vs 58.5%) and 10 years (48.5% Vs 42.7%) the survival was similar. Compartmentalized gut CMV was associated with a higher relapse rate (19.5%) when compared with CMV diarrhoea (6.4%) on follow-up (p = 0.06). The mortality (36% Vs 29%; p = 0.490) and graft loss (25% Vs 22%; p = 0.692) were similar between both the group. Conclusion Compartmentalized gut invasive CMV represents a larger proportion of chronic diarrhoeal illness with a higher relapse rate, which needs invasive gut tissue PCR analysis, despite negative blood PCR, for early diagnosis and management.

Incidence and severity of cytomegalovirus infection in seropositive heart transplant recipients.

The frequency and significance of cytomegalovirus (CMV) infection in seropositive (R+) heart transplant recipients (HTR) is unclear, with preventative recommendations mostly extrapolated from other groups. We evaluated the incidence and severity of CMV infection in R+ HTR, to identify risk factors and describe outcomes. R+ HTR from 2010 to 2019 were included. Antiviral prophylaxis was not routinely used, with clinically guided monitoring the local standard of care. The primary outcome was CMV infection within one-year post-transplant; secondary outcomes included other herpesvirus infections and mortality. CMV infection occurred in 27/155 (17%) R+ HTR. Patients with CMV had a longer hospitalization (27 vs. 20 days, unadjusted HR 1.02, 95% CI 1.00-1.02, p=.01), higher rate of intensive care readmission (26% vs. 9%, unadjusted HR 3.46, 1.46-8.20, p=.005), and increased mortality (33% vs. 8%, unadjusted HR 10.60, 4.52-24.88, p<.001). The association between CMV and death persisted after adjusting for multiple confounders (HR 24.19, 95% CI 7.47-78.30, p<.001). Valganciclovir prophylaxis was used in 35/155 (23%) and was protective against CMV (infection rate 4% vs. 27%, adjusted HR .07, .01-.72, p=.025), even though those receiving it were more likely to have received thymoglobulin (adjusted OR 10.5, 95% CI 2.01-55.0, p=.005). CMV infection is common in R+ HTR and is associated with a high burden of disease and increased mortality. Patients who received valganciclovir prophylaxis were less likely to develop CMV infection, despite being at higher risk. These findings support the routine use of antiviral prophylaxis following heart transplantation in all CMV R+ patients.

Fatal HSV-2 primary infection most likely acquired by kidney transplantation: A case report

Herpes simplex virus 2 (HSV-2) rarely causes severe disease, even in solid organ transplant recipients. This paper describes a fatal case of HSV-2 infection, probably transmitted from a donor to a kidney transplant recipient. The donor was seropositive for HSV-2 but not for HSV-1, whereas the recipient was seronegative for both viruses before transplantation, suggesting that the graft was the source of infection. The recipient received valganciclovir prophylaxis due to cytomegalovirus seropositivity. Three months after transplantation, the recipient presented with rapidly disseminated cutaneous HSV-2 infection with meningoencephalitis. The HSV-2 strain was resistant to acyclovir, probably acquired under valganciclovir prophylaxis. Despite early initiation of acyclovir therapy, the patient died. This fatal case of HSV-2 infection, probably transmitted by the kidney graft with acyclovir-resistant HSV-2 from the onset, is uncommon.

Impact of high MELD scores on CMV viremia following liver transplantation.

Advanced liver disease or cirrhosis is associated with an increased risk of infections; however, the impact of high pretransplant model for end-stage liver disease (MELD) score on cytomegalovirus (CMV) viremia after liver transplantation is unknown. This single-center, retrospective, cohort study evaluated CMV high-risk (CMV immunoglobulin G D+/R-) liver transplant recipients who received valganciclovir prophylaxis for 3 months between 2009 and 2019. Patients were stratified by pretransplant MELD score of <35 (low MELD) and ≥35 (high MELD). The primary outcome was 12-month CMV viremia, and secondary outcomes included CMV resistance and tissue invasive disease, mortality, biopsy-proven acute rejection (BPAR), leukopenia, and thrombocytopenia. Multivariable Cox proportional-hazards modeling was used to assess the association of MELD score with the time to CMV viremia. There were 162 and 79 patients in the low and high MELD groups, respectively. Pretransplant MELD score ≥35 was associated with an increased risk of CMV viremia (hazard ratio [HR] 1.73; confidence interval 1.06-2.82, p=.03). CMV viremia occurred at 162±61 days in the low MELD group and 139±62 days in the high MELD group. Although BPAR occurred early at 30 days (13-59) in the low-MELD group and at 18 days (11-66) in the high-MELD group (p=.56), BPAR was not associated with an increased risk of CMV viremia (HR 1.55 [0.93-2.60], p=.1). MELD scores ≥35 were associated with an increased hazards of CMV viremia. In liver transplant recipients with MELD scores ≥35 who are CMV high-risk, additional CMV intervention may be warranted.

210. Neutropenia and Associated Infectious Complications Among Kidney Transplant Recipients Receiving Valganciclovir Prophylaxis in the United States: An Administrative Claims Database Study

Abstract Background Valganciclovir (VGCV) prophylaxis is commonly utilized to prevent cytomegalovirus (CMV) infection among high (D+/R-) and intermediate (R+) risk kidney transplant recipients (KTRs). Due to the myelosuppressive effects of VGCV, KTRs may be at an increased risk of opportunistic infections (OIs) resulting in interruptions to VGCV therapy. Therefore, we aimed to quantify the clinical burden of neutropenia among adult KTRs receiving VGCV prophylaxis. Methods A retrospective cohort design was utilized to identify adult KTRs who received VGCV prophylaxis using the IBM MarketScan Commercial and Medicare Supplemental claims databases. First-time KTRs between 1/1/2012 - 12/31/2018 with 1 year of continuous pharmacy and medical coverage before (baseline period) and after (follow-up period) were included. KTRs with a History of other solid organ transplantation were excluded. Fills of ≥ 1 prescription of VGCV (either 450 mg or 900 mg/day) within 30 days of the kidney transplant (KT). Neutropenia events were identified as either ≥ 1 inpatient, or ≥ 2 outpatient ICD-9/ICD-10 diagnoses codes within 14 days. Results Of the 4,965 adults KTRs with baseline and follow-up enrollment, 3,258 (66%) used VGCV prophylaxis. 311/3256 (9.5%) developed neutropenia within 1-year post KT. Baseline characteristics were similar between those with and without neutropenia (table 1). The majority received the following pre-transplant immunosuppression: tacrolimus (78.9%), mycophenolate mofetil (62.8%) and steroids (prednisone, 79.3%, methylprednisolone 10.6%). KTRs with neutropenia had a nearly two-fold increase in the development of CMV infection compared to those without neutropenia. In addition, KTRs with neutropenia had significantly higher rate of bacterial or fungal infections compared to those without neutropenia (Table 2). Interruptions in VGCV prophylaxis (gap &amp;gt;15 days) were more common in KTRs with neutropenia (P&amp;lt; 0.001). Conclusion Our findings showed that neutropenia was associated viral, bacterial, and fungal OIs among adults KT receiving VGCV prophylaxis. The findings highlight the needs for interventions to reduce neutropenia and its associated OIs. These results suggest that clinical management steps to reduce rates of neutropenia among KT recipients may warrant further study. Disclosures Vladimir Turzhitsky, PhD, Merck &amp; Co., Inc.,: Employee|Merck &amp; Co., Inc.,: Stocks/Bonds Amit D. Raval, PhD, Merck and Co., Inc.: Employee of Merck|Merck and Co., Inc.: Stocks/Bonds Pamela Moise, PharmD, Merck &amp; Co., Inc: Employee &amp; Shareholder Sanjay Merchant, PhD, Merck &amp; Co., Inc.: Stocks/Bonds.

Incidence and Severity of Cytomegalovirus Infection in Seropositive Heart Transplant Recipients

<h3>Purpose</h3> Cytomegalovirus (CMV) infection contributes to morbidity and mortality in heart transplant recipients (HTR). Donor positive, recipient negative (D+/R-) patients are high risk and generally receive antiviral prophylaxis. The burden of CMV infection in recipient seropositive (R+) HTR is less clear, with preventative recommendations mostly extrapolated from other solid organ transplant groups. The aim of this retrospective cohort study was to define the incidence, severity of & risk factors for CMV infection in R+ HTR. <h3>Methods</h3> CMV seropositive HTR were included (2010-2019). Antiviral prophylaxis was not routinely used, with clinical monitoring the local standard of care. Data were collected from medical records, & patients followed for a year post-transplant. The incidence of CMV infection, including tissue invasive disease, was quantified, & predisposing/mitigating factors identified. We also assessed the association of CMV with adverse outcomes including prolongation of hospitalization & death. <h3>Results</h3> Our cohort included 155 R+ HTR (median age 53yrs, 72% male, 56% D+/R+, 68% basiliximab & 8% thymoglobulin induction). Valganciclovir prophylaxis was used in 35 (23%) for a median of 103 days (IQR 78-222). CMV infection occurred in 27 (17%) patients at a median onset of 67 days (41-124), median peak viral load was 1250 IU/mL (221-6539) & 18/27 (67%) required readmission. End-organ disease occurred in 22 (82%) & was most commonly gastrointestinal (52%). CMV infection was associated with a longer length of stay (27 vs. 20 days, HR 1.02, 95% CI 1.00-1.03, p=0.02), higher rate of intensive care readmission (26% vs. 9%, 4.57, 1.76-11.88, p=0.002), & increased mortality (33% vs. 8%, HR 9.11, 3.49-23.8, p<0.001). Valganciclovir prophylaxis was protective for CMV (4% vs. 27%, 0.094, 0.012-0.75, p=0.025), even though patients receiving it were more likely to have had thymoglobulin induction (31% vs. 2%, OR 27.04, 5.63-129.88, p<0.001). <h3>Conclusion</h3> CMV infection occurred in 17% of R+ HTR & was associated with a high burden of disease, worse post-transplant outcomes & increased mortality. Patients who received valganciclovir prophylaxis were less likely to develop CMV infection. These findings support the routine use of CMV preventative strategies such as antiviral prophylaxis following heart transplantation in all CMV R+ patients.

Risk Assessment of Neutropenia during Low-Dose Valganciclovir Prophylaxis for Heart Transplant Recipients.

The aim of this study was to investigate whether low-dose valganciclovir (VGCV) prophylaxis for cytomegalovirus (CMV) infection increased the risk of developing neutropenia in heart transplant recipients (HTRs). Forty-three HTRs receiving VGCV were divided into two groups: those who received VGCV prophylaxis (n = 22) and those who did not (n = 21). Neutropenia was defined as an absolute neutrophil count ˂1500/µL and was monitored for approximately one year post-transplantation. In the prophylaxis group, 77.3% (17/22) of HTRs experienced neutropenia, which was significantly higher than that in the no prophylaxis group (42.9% [9/21], p = 0.031). No significant differences in the duration of VGCV administration and cumulative dose up to the first neutropenia episode were observed between the groups. Meanwhile, the cumulative dose of mycophenolate mofetil was significantly higher in the prophylaxis group than in the no prophylaxis group (p = 0.018); the daily maintenance dose and regularly measured area under the concentration-time curve (AUC) of mycophenolic acid did not significantly differ between groups. In conclusion, the risk of developing neutropenia was higher in HTRs receiving low-dose VGCV prophylaxis than it was in those not receiving prophylaxis, probably not attributed to dosing period and cumulative dose of VGCV until the onset of neutropenia.

Safety of Valganciclovir 450 mg 3 Times Weekly for Cytomegalovirus Prophylaxis in Solid Organ Transplant Recipients Requiring Hemodialysis.

BackgroundValganciclovir is the most commonly used antiviral for cytomegalovirus (CMV) prophylaxis in solid organ transplant recipients. However, there are limited clinical outcomes-supported data available to guide valganciclovir dosing in patients on hemodialysis (HD). This study aimed to assess the safety of our institution’s current dosing strategy of valganciclovir 450 mg 3 times weekly post-HD.MethodsThis was a single-center retrospective review of all adult nonkidney transplant recipients between May 2016 and June 2018. Patients with end-stage renal disease requiring HD for >28 days posttransplant receiving valganciclovir 450 mg 3 times weekly post-HD were matched with non-HD patients receiving valganciclovir prophylaxis dosed per renal function. The primary endpoints were incidence of leukopenia, neutropenia, and thrombocytopenia while on valganciclovir prophylaxis.ResultsA total of 465 nonkidney transplants were performed during the study period, with 37 patients included in the HD group who were matched to 111 control patients in the non-HD group. Liver transplant recipients comprised 84% and 72% of each group, with none being CMV D+/R−. The rates of leukopenia (51.4% vs 51.4%, P = 1.00), severe neutropenia (absolute neutrophil count <500 cells/µL, 15.8% vs 14.0%, P = .85), and thrombocytopenia (24.3% vs 20.7%, P = .64) were similar in both HD and non-HD groups. There were no cases of CMV infection while on valganciclovir prophylaxis in either group.ConclusionsValganciclovir 450 mg 3 times weekly was found to have similar rates of leukopenia, neutropenia, thrombocytopenia, and CMV infection in comparison to valganciclovir dosed per renal function in non-HD transplant recipients.

Development of CMV‐specific cytotoxic T cells (CMV‐Tc) in pediatric renal transplant recipients with CMV viremia

Viral infections are controlled primarily by viral-specific T cells, raising concern for adequate T-cell response to clear CMV infection in transplant recipients receiving lymphocyte-depleting agents (LDA). We examined the rates of CMV viremia and clearance, seroconversion, and CMV-specific CD8+ T cell (CMV-Tc) activity with class of induction agent received. Retrospective review of 45 pediatric renal transplant recipients who received induction with LDA (n=31) or non-LDA (NLDA; n=14) received valganciclovir prophylaxis for 6months post-transplant and CMV-PCR monitoring. CMV-Tc was measured by intracellular IFNγ flow cytometry, when possible, at baseline, 1month after CMV viremia (>5 copies/PCR) and serially until CMV-Tc was positive (≥0.2%). Viremia rates at 1, 2, and 4years post-transplant were higher in LDA vs. NLDA (46.3% vs. 7.2%, 64.2% vs. 7.2%, and 64.2% vs. 7.2%, respectively; p=.002). Viremia rates at these time points in seronegative LDA (50.3%, 71.6%, 71.6%) were significantly or near significantly higher than seronegative NLDA (9.1%, 9.1%, 9.1%; p=.004), seropositive-LDA (22.3%, 22.3%, 22.3%; p=.07), or seropositive NLDA (0%, 0%, 0%; p=.07). Eleven of 17 (64.7%) viremic subjects required valganciclovir dose reduction during the prophylaxis period for leukopenia. All viremic LDA patients developed CMV-Tc. One viremic NLDA patient did not develop CMV-Tc. No patients developed CMV disease. CMV seronegative pediatric renal transplant patients receiving LDA are more likely to have valganciclovir prophylaxis dose reduction and develop subclinical CMV viremia; however, all developed CMV-Tc. Larger prospective studies are needed to further understand the effects of induction agents on CMV-Tc and CMV-Tc's role post-transplant.

Cytomegalovirus Infections are Frequent after Heart Transplantation but Do Not Increase the Risk of Biopsy-Proven Allograft Rejection in the Modern Era

Our aim was to analyze the clinical impact of CMV infections on the risk of allograft rejection. We conducted a single-center retrospective study including patients transplanted between January 2012 and December 2016 who had at least one endomyocardial biopsy (EMB) during follow-up. Patients at high risk of CMV infections (D+/R-) received valganciclovir prophylaxis for 3 months, those at intermediate risk (R +) were treated according to a preemptive strategy (viral replication threshold: 10,000 IU / mL). Protocol monitoring included 13 B.M. per patient in the first year. Allograft rejection was defined as ≥ 1R1B acute cellular rejection or ≥ pAMR1 antibody-mediated rejection according to international guidelines. The impact of CMV infection, defined as a viral replication ≥ 10,000 IU / mL, on the risk of allograft rejection was analyzed using a mixed effects logistic regression. 399 patients met the inclusion criteria, including 60 patients D+/ R-, 256 R+ and 72 D+/R. All patients received an induction therapy and a triple basal immunosuppression. We observed a dynamic risk of infection during the first year according to the baseline CMV serology (Figure 1A). CMV infections were diagnosed in more than half of the patients (Figure 1B). 140 patients (35%) had at least one episode of biopsy-proven rejection. In univariable analyses, CMV infections were not associated with an increased risk of rejection in month following infection (0R=1.03, 95%CI=0.6-1.7, p=0.91). After adjustment for the presence of DSA, the number of HLA AB-DR-DQ mismatches, recipient age and time post-transplant, CMV infections were not associated with the risk of rejection in month following infection (OR=0.9, 95%CI=0.5-1.5, p=0.61). Different timing post-infection have been evaluated but were not associated with rejection. CMV infections were common after heart transplantation but were not associated with the risk of allograft rejection.

Prevalence of human herpesviruses in biliary fluid and their association with biliary complications after liver transplantation

BackgroundBeta-herpesviruses are common opportunistic pathogens that cause morbidity after liver transplantation (LT).MethodsObjective of the study was to evaluate the prevalence and correlation of herpesviruses in bile, blood and liver tissue and to investigate their association with biliary complications and retransplantation (re-LT) free survival after LT.The study design is a single-center case-control study. We performed quantative polymerase chain reaction (qPCR) for herpesvirus 1–8 DNA in bile, blood and liver tissue of 73 patients after first LT and analyzed their clinical courses retrospectively.ResultsThe median follow-up was 48 months (range 2–102), during which a total of 16 patients underwent re-LT and 11 patients died. Of the patients, 46.5% received valganciclovir prophylaxis at the time of bile sample acquisition. Cytomegalovirus (CMV) (18.3%), human herpesvirus 6 (HHV-6) (34.2%), human herpesvirus 7 (HHV-7) (20.5%) and Epstein-Barr virus (EBV) (16.4%) were highly prevalent in bile after LT, while herpes simpex virus 1 and 2 (HSV-1, HSV-2), varicella-zoster virus (VZV) and human herpesvirus 8 (HHV-8) were not or rarely detected in bile. Valganciclovir prophylaxis did not reduce the prevalence of HHV-6 and HHV-7 in bile, but it did reduce the presence of CMV and EBV. The presence of HHV-6 in bile was associated with non-anastomotic biliary strictures (NAS) and acute cellular rejection (ACR).ConclusionsCMV, EBV, HHV-6 and HHV-7 are more prevalent in biliary fluid than in liver biopsy or blood serum after LT. HHV-6 and HHV-7 might be associated with biliary complications after LT. Biliary fluids might be an attractive target for routine herpesvirus detection.

Clinical outcomes of valganciclovir prophylaxis in high-risk (D+/R-) renal transplant recipients experiencing delayed graft function.

Cytomegalovirus (CMV) outcomes with valganciclovir prophylaxis in renal transplant recipients experiencing delayed graft function (DGF) are unclear. This single center, retrospective, cohort study of CMV high-risk (D+/R- with alemtuzumab induction) deceased donor renal transplant recipients receiving valganciclovir prophylaxis assessed CMV outcomes in patients experiencing DGF (n=72) versus those with immediate graft function (IGF; n=66). Cytomegalovirus viremia by 12months occurred at similar rates in the IGF and DGF groups (30.3% vs 26.4%, respectively, P=0.71) with 89.7% (35/39) of all cases classified as CMV disease. The median time to CMV viremia post transplant was day 141 and 138 in the IGF and DGF groups, respectively (P=0.30). The incidence of biopsy-proven acute rejection (BPAR) was higher in the DGF group (18.1% vs 4.6%, P=0.02) with BPAR preceding CMV in only 1 patient. There was no significant difference in graft loss (1.5% vs 4.2%, P=0.62) or patient survival (98.5% vs 95.8%, P=0.62) at 1 year between the IGF and DGF groups, respectively. Valganciclovir prophylaxis in patients experiencing DGF yielded similar CMV outcomes up to 1-year post transplant when compared to use in patients with IGF.

Cytomegalovirus Infection among Pediatric Heart Transplant Recipients in the Current Era of Valganciclovir Prophylaxis: Impact on Post-Transplant Outcomes

Purpose To study the relation between the presence and absence of asymptomatic CMV infection in the first year after heart transplant (HT) and subsequent rejection, cardiac allograft vasculopathy (CAV) and graft loss in the era of valganciclovir prophylactic treatment . Methods Retrospective study of 97 pediatric HT recipients between 2010 and 2016, pre- and post-HT variables were extracted from electronic medical records . Asymptomatic CMV infection was defined as quantifiable CMV PCR value of >1000 copies/ml and/or positive anti-CMV antibody by immunofluorescence (IFA) in myocardial samples during first year of HT. Results Total 42 pediatric HT recipients (43%) received valganciclovir prophylaxis. Overall, 34% (33/97) of patients developed asymptomatic CMV infection within one year following transplant. Valganciclovir prophylaxis decreased the number of CMV-PCR positive infections (p myocardium (p= 0.001) (Figure-2). Individuals with CMV infection were at increased rate of allograft rejections after one year compared to those with no CMV infection (p = 0.009). However, incidence of CAV and graft loss after first year of HT with or without CMV infection was not significant (log-rank p = 0.233 and p = 0.4, respectively). Conclusion Our study supports the emerging evidence that valganciclovir prophylaxis prevent CMV infection in pediatric HT recipients and may be helpful in reducing long-term complications such as CAV and graft loss.

1564. Lower Rates of Epstein–Barr Virus (EBV) Viremia in Pediatric Solid Organ Transplant (SOT) Recipients Who Received Valganciclovir Prophylaxis

BackgroundAntiviral prophylaxis to prevent PTLD remains controversial, but some data suggest that valganciclovir or ganciclovir ([val]ganciclovir) use in EBV high-risk pediatric renal transplants reduces EBV viremia. We evaluated the impact of [val]ganciclovir on EBV viremia and post-transplant lymphoproliferative disease (PTLD) in pediatric nonrenal SOT recipients.MethodsRetrospective study of 100 patients who underwent a first heart, liver, lung, intestine, or multivisceral SOT between November 2013 and November 2016 at Boston Children’s Hospital who survived without re-transplantation for at least 30 days. Data collected included EBV donor/recipient serostatus, donor’s age >2 years-old (to avoid misclassification of EBV risk due to maternal antibody), antiviral use ([val]ganciclovir or acyclovir), time to EBV viremia (>1,000 copies/mL by whole blood PCR), and time to development of PTLD. EBV high-risk patients were those with donor EBV positive [D+]/recipient EBV negative [R–] serologies; intermediate-risk were EBV R+; low risk were EBV D–/R–. Time-to-event analysis using the Kaplan–Meier method was performed and significance (P = 0.05) was evaluated using the log-rank test.ResultsHigh (n = 45) or intermediate (n = 27) EBV risk was associated with increased EBV viremia (P = 0.007, table). EBV viremia was significantly decreased in the subgroup of high-risk patients with donors >2 years old who received [val]ganciclovir vs. those who received no antiviral (n = 23, n = 4, P = 0.03, Figure 1). Most PTLD cases (8/9) occurred in the high-risk group (P = 0.03, Figure 2). Overall, patients who received [val]ganciclovir had less PTLD than those who did not (P = 0.03), but this was not significant in the high-risk subgroup (P = 0.14, Figure 3).ConclusionLower rates of EBV viremia occurred in high EBV risk transplant recipients who received [val]ganciclovir, possibly by preventing primary EBV infection. Recipients with high EBV risk have the highest rate of PTLD.cases=100EBV RiskOutcomeOrganUnknownLowIntermediateHighViremiaPTLDHeart581320185Liver11101862Lung114462Intestine10Multivisceral11Dual organ31Total7212745439AntiviralNo Antiviral6652Acyclovir213873[Val]ganciclovir5132431314OutcomeViremia2214259PTLD189 Disclosures F. M. Marty, Merck: Consultant and Investigator, Consulting fee, Research support and Speaker honorarium; Astellas: Consultant and Investigator, Consulting fee and Research support; Chimerix: Consultant and Investigator, Consulting fee and Research support; Fate Therapeutics: Consultant, Consulting fee; GlaxoSmithKline: Consultant, Consulting fee; LFB: Consultant, Consulting fee; Roche Molecular Diagnostics: Consultant, Consulting fee; Shire: Consultant and Investigator, Consulting fee and Research support.

Valganciclovir Pharmacokinetics in Patients Receiving Oral Prophylaxis Following Kidney Transplantation and Model-Based Predictions of Optimal Dosing Regimens.

Valganciclovir is used as oral prophylaxis for cytomegalovirus (CMV) infection in kidney transplant recipients. However, limited pharmacokinetic data exist to guide dosing in this patient group. This study aimed to describe the population pharmacokinetics of valganciclovir in a large sample of kidney transplant recipients and predict optimal dosing based on Monte Carlo simulations. Therapeutic drug monitoring (TDM) data from adult kidney transplant recipients who received valganciclovir prophylaxis during a 10-year study period were collected retrospectively. A non-parametric pharmacokinetic analysis and Monte Carlo simulations to determine the probabilities of reaching an area under the drug concentration-time curve (AUC) target of 40-50mg·h/L with various dosing regimens at different levels of renal function were conducted using the Pmetrics™ package for R. This study included 792 ganciclovir concentration measurements derived from 97 patients. A one-compartment oral absorption model best described the data. The final covariate model was as follows: CL(ganciclovir)=TVCL×(CLCR/51)0.75, where CL is the clearance, TVCL is the typical value of ganciclovir clearance, creatinine clearance (CLCR) according to the Cockcroft-Gaultt equation and 51 is the mean CLCR determined in the study. In the simulations, the probability of reaching the targeted AUC was insufficient when using the recommended dosing regimens for prophylaxis, especially in patients with impaired renal function at CLCR<50mL/min. Higher doses of valganciclovir corrected to renal function are suggested for use as oral prophylaxis for CMV infection in kidney transplant recipients. Further study is required to establish TDM targets to ensure adequate drug concentrations while avoiding potentially toxic drug exposures.

High frequency of valganciclovir underdosing for cytomegalovirus prophylaxis after renal transplantation.

BackgroundThe correct valganciclovir dose for cytomegalovirus (CMV) prophylaxis depends on renal function estimated by the Cockcroft–Gault (CG) estimated creatinine clearance (CG-CrCl) formula. Patients with delayed or rapidly changing graft function after transplantation (tx) will need dose adjustments.MethodsWe performed a retrospective investigation of valganciclovir dosing in renal transplant patients receiving CMV prophylaxis between August 2003 and August 2011, and analysed valganciclovir dosing, CG-CrCl, CMV viraemia (CMV-PCR <750 copies/mL), leucopenia (<3500/µL) and neutropenia (<1500/µL) in the first year post-transplant. On Days 30 and 60 post-transplant, dosing pattern in relation to estimated creatinine clearance was analysed regarding CMV viraemia, leucopenia and neutropenia.ResultsSix hundred and thirty-five patients received valganciclovir prophylaxis that lasted 129 ± 68 days with a mean dose of 248 ± 152 mg/day of whom 112/635 (17.7%) developed CMV viraemia, 166/635 (26.1%) leucopenia and 48/635 (7.6%) neutropenia. CMV resistance within 1 year post-transplant was detected in three patients. Only 137/609 (22.6%) patients received the recommended dose, while n = 426 (70.3%) were underdosed and n = 43 (7.1%) were overdosed at Day 30 post-tx. Risk factors for CMV viraemia were donor positive D (+)/receptor negative R (−) status and short prophylaxis duration, but not low valganciclovir dose. Risk factors for developing leucopenia were D+/R− status and low renal function. No significant differences in dosing frequency were observed in patients developing neutropenia or not (P = 0.584).ConclusionMost patients do not receive the recommended valganciclovir dose. Despite obvious underdosing in a large proportion of patients, effective prophylaxis was maintained and it was not associated as a risk factor for CMV viraemia or leucopenia.

Prolonged Low-Dose Prophylaxis With Valganciclovir in Cytomegalovirus-Negative Recipients of Kidney Transplants From Cytomegalovirus-Positive Donors Allows Seroconversion and Prevents Cytomegalovirus Disease

BackgroundCytomegalovirus-negative recipients of kidneys from cytomegalovirus (CMV)-positive donors (D+/R−) are at high risk to develop severe clinical manifestations of CMV disease. Long-term data about incidence and timing of CMV seroconversion, CMV disease, and the influence of prolonged valganciclovir prophylaxis on the clinical course of CMV infection are missing. MethodsWe conducted a retrospective long-term study of 89 consecutive CMV D+/R− kidney transplant recipients transplanted between 2003 and 2012. All recipients received valganciclovir prophylaxis after transplantation (median 187 [126-261] days) with a median dose of 213 (181-338) mg/d. Long-term outcome was assessed over a maximum of 10 years post-transplant. ResultsDuring follow-up (median 62 months) 60 of 89 (67%) patients had CMV seroconversion, and 29 of 89 (33%) developed symptomatic CMV disease. In addition, in 38 of the 60 (63%), seroconversion occurred during prophylaxis (median 154 days post-transplant), and in 22 patients, after the end of prophylaxis (median 320 days after transplantation). Baseline characteristics of the 2 groups did not differ significantly. Seroconversion during prophylaxis vs seroconversion after the end of prophylaxis was associated with significantly lower incidence of CMV disease (34% vs 73%, P = .007), less severe CMV disease (16% vs 64%, P < .001), and fewer organ manifestations (26% vs 64%, P = .006). The risk of CMV disease was limited to the first 475 days after transplantation. Valganciclovir resistance occurred in just 1 case (1%). ConclusionsProlonged prophylaxis with low-dose valganciclovir allowed CMV seroconversion during prophylaxis in a high proportion of D+/R− patients. Seroconversion occurred after a median of 154 days and was associated with significantly lower incidence of CMV disease, less severe CMV disease, and fewer CMV complications.