Correction: Clinical management and burden of cytomegalovirus in D+/R-Kidney transplant recipients in Canada

Cytomegalovirus (CMV) infection is a common complication of kidney transplantation which remains a major therapeutic challenge with both clinical and economic implications (1,2). The risk of CMV infection is highest in immunologically naïve seronegative recipients (R-) of organs from a seropositive donor (D+), comprising approximately 10% to 20% of kidney transplants (3)(4)(5). Anti-viral prophylaxis has reduced and delayed the risk of CMV infection in these patients (5)(6)(7)(8)(9), which occurs in 10 -50% (3,(10)(11)(12) of subjects throughout the first post-transplant year (1).CMV infection may present with a broad range of disease expression from asymptomatic viremia to CMV syndrome or end-organ disease including esophagitis, enteritis, pneumonitis, encephalitis, pancreatitis, and other target organ damage (8). It may occur alone, or in a complex context of multiple disease events. For example, CMV is often diagnosed coincident with other bacterial, viral or fungal opportunistic infections in the posttransplant setting, complicating diagnosis, and management (13)(14)(15). The occurrence of CMV infection and graft rejection are also closely correlated, and models of combinatorial risk have been proposed (16). However, it remains unclear whether the immune modulating effect of the virus enhances graft rejection, or treatment of rejection increases the risk of viremia (8,17).Despite overall reduction in the incidence, severity, and consequences of CMV infection, the management of D+/Rpatients remains challenging. CMV viremia and disease occur more commonly within this group and may result in serious complications, despite current prophylaxis strategies (1,5,18,19). Prolonged prophylaxis can itself have important costs and toxicity resulting in serious clinical leukopenia (20) which may in turn lead to co-infection or secondary reduction in immune suppression resulting in breakthrough rejection.Measurement of CMV viral load is considered the most relevant index to document viral replication, to diagnose infection, and to determine treatment effect. It has also been included as a surrogate marker in clinical trial settings (1,7,8,21). Accurate monitoring of viral load and the use of anti-viral prophylaxis or pre-emptive therapy have mitigated the lethal consequences of CMV infection and diminished the early indirect consequences and costs of care (1,8). Calculation of viral load kinetics has been proposed to guide the frequency of sample measurement and to facilitate the effective use of therapy (22,23), but this has not yet been incorporated into clinical practice.Despite the availability of US, European and international clinical guidelines, we lack current Canadian published data on the clinical treatment and burden of CMV infection as we optimize management strategies for preventing infection in this high-risk kidney transplant population (8,(24)(25)(26). The recommendations of the Canadian Society of Transplantation CMV Consensus Working Group were published almost two decades ago (27) and a more recent single-center Canadian pediatric study (28) does not provide evidence that is applicable to the broader landscape of transplantation. Consequently, viral testing, prophylaxis or preemptive therapies vary between transplant programs.The goal of this study was to complement existing knowledge in both live donor (LD) and deceased donor (DD) D+/R-patients who were at highest risk for CMV infection and disease by providing a comprehensive understanding of current practice, to understand disease burden, provide precise and current data for economic modeling, and to highlight opportunities to improve therapy and healthcare resource utilization in this patient population. We report the dynamics and cumulative frequencies of the key outcomes of interest which will enable us to model the interplay of these events and identify groups with differential disease burden to guide therapy.The primary objectives of this study were to describe: (a) the incidence of CMV infections (including but not limited to: reactivations, number of recurrences as well as incidence of resistant or refractory infection or disease); (b) incidence of CMV antiviral-related myelotoxicities, including leukopenia and neutropenia, and their impact on patient's treatment adjustments (decrease/discontinuation of immunosuppressants and CMV antiviral agents); and (c) the association of CMV management with health care resource utilization (HCRU), including the length of hospital stay (LOS) and frequency of hospital admissions.This retrospective, consecutive subject, multicenter cohort study was designed to examine the clinical and economic burden and unmet prophylactic needs in CMV seronegative adult recipients (R-) 18 years or older of a kidney transplant from a CMV seropositive donor (D+). Recipients who participated in an interventional trial in the prior 90 days, had received another organ or stem-cell transplant, or were exposure to letermovir were excluded. The study was conducted in seven major transplant centers in Canada (Table 1) and included consecutive CMV seronegative recipients in each participating transplant program who received a kidney transplant from a CMV seropositive donor from January 1st, 2018 to December 31st, 2021, and for whom continuous follow-up data were available. A pragmatic sample of approximately 300 CMV D+/R-kidney transplant recipients was considered adequate to provide preliminary evidence of CMV treatment and burden.The index date for each participant was the date of kidney transplant (Day 0) and data were recorded for the first year following transplantation. Primary data elements included, but were not limited to, patient demographics (age, age at time of first kidney transplant, race, proximity to transplant center); donor source (living/ deceased), HLA matching; clinical therapies including induction regimen; CMV infection, syndrome, or disease; the incidence and management of CMV antiviral-related myelotoxicities; and healthcare resource use. Secondary data elements included time to CMV infection, viremia levels, viral load kinetics; event history (phlebitis, anemia, thrombocytopenia, pancytopenia, neutropenia, direct renal tubular toxicity, crystalline nephropathy, leukopenia, other); non-CMV opportunistic infections; graft outcomes; utilization patterns of CMV therapy; and incidence and management of other CMV antiviralrelated toxicities.The following characteristics were extracted from the patient charts to describe antiviral prophylaxis and treatment for CMV: whether anti-viral prophylaxis treatment was prescribed; the stage of use (primary [immediate post-transplant] or secondary [postprimary infection]); and the type of antiviral medication including the dose, unit; frequency and start and stop dates. The response of CMV infection to antiviral treatment was measured using the following data obtained from the patient chart: the date of the first episode of CMV infection; the duration of the episode (days); any change in treatment; (immunosuppression, antiviral prophylaxis, G-CSF, other); whether resistant or refractory CMV Infection or disease occurred (yes/no); and whether resistant infection or disease was confirmed (yes/no).Myelotoxicity (determined as hematological values below the lower level of normal for each institution) and other adverse consequences of antiviral treatment were recorded using measures obtained from the patient chart. These included: whether CMV antiviral related myelotoxicities occurred (yes/no); the type of myelotoxicity (neutropenia, leukopenia, thrombocytopenia, pancytopenia); other antiviral toxicity recorded (nephrotoxicity, neurotoxicity, electrolyte disturbance, other); grading of the severity (using the NCI-CTCAE Grade 1 -5) (29); whether toxicity was drug related (yes/no) and if so the drug name (ganciclovir, foscarnet sodium, immunoglobulin, valganciclovir, other); and any change in treatment (immunosuppression, antiviral prophylaxis, G-CSF, other).CMV infection was measured as: (a) the incidence of the first and of each subsequent CMV episode post-transplant, including any combination of CMV infection, CMV syndrome and CMV disease; (b) the time in days to start of the first CMV reactivation (infection, syndrome or disease if noted prior to documented infection) and to each subsequent CMV infection post-transplant; and (c) the peak viral load during first and each subsequent CMV infection post-transplant.CMV syndrome was defined as viremia accompanied by the presence of classical features of CMV infection including fever, malaise, leukopenia, thrombocytopenia, elevated hepatic transaminases and greater than or equal to 5% atypical lymphocytes (30).CMV end-organ disease was defined as viremia, which was accompanied by gastrointestinal disease, pneumonitis, hepatitis, nephritis, myocarditis, pancreatitis, encephalitis, retinitis, pulmonary or other classical features of organ involvement (30).Unmet needs of current prophylaxis were measured as: (a) the incidence of CMV prophylaxis, the descriptions of medications used and the duration of therapy; (b) the incidence of CMV treatment for CMV infection, the description of medications used and the duration of therapy; (c) the incidence and management of CMV antiviral related myelotoxicities and patient outcome associated with neutropenia/leukopenia and (d) the incidence and management of other CMV antiviralrelated toxicities (e.g., nephrotoxicity).Health economic burden was measured as; (a) the incidence and length of stay of all cause hospitalizations, ICU admissions, hospitalization for CMV infection, and hospitalizations associated with neutropenia/leukopenia and their consequences; (b) the number of health care visits post-transplant with a general practitioner, nephrologist and/or urologist; (c) the frequency of CMV surveillance post-transplant (e.g. PCR tests, in-person visits); (d) the number of re-admissions for CMV related morbidity; (e) CMV antiviral therapy and duration of treatment; (f) the incidence and use of Granulocyte Colony Stimulating Factor (GCSF); and (g) the proximity of the patient to the primary transplant hospital to assess feasibility of in-person follow-up visits.Graft outcome and patient survival were assessed from the incidence and type of graft rejection, graft dysfunction and graft loss based on normal clinical, laboratory and histological parameters. Patient survival was measured using the following data from the patient chart: whether the patient was alive at end of follow up period (yes/no); if no, the date of patient death; and the primary cause of death (i.e. CMV disease, related to CMV including documented CMV infection at death, or other complications relating to the patients transplant surgery, cardiovascular event, other events, or unknown).All analyses were performed based on the Eligible Population (ELIG) which was a subset of all enrolled participants with complete data available for 365 days, or to the point of death or graft loss. Descriptive statistics were produced for all key study variables for the overall study population. Demographic data included baseline recipient characteristics. Therapeutic data included immunosuppressive therapy, anti-viral prophylaxis and treatment, and other principal therapies that could influence outcome or disease prevalence. Clinical and laboratory data included CMV Ig status at the time of transplant, quantitative viremia, CMV syndrome and disease, graft and participant survival and other outcome variables of interest.Continuous variables were summarized using the number of non-missing observations, mean, standard deviation (SD), median, minimum, and maximum values and interquartile ranges. Categorical variables were summarized using the number and percentage of participants belonging to each category. Event rates (summarized as the number of participants experiencing that event) and incidence rates (summarized as the total number of events in a group divided by the time at risk), were summarized within the study population and sub-populations of interest for all the dependent variables (e.g. CMV viremia, CMV resistance, developing refractory CMV). Time to event endpoints were calculated using the Kaplan-Meier estimator, and differences between groups were evaluated using the log-rank test. Analysis was performed using SAS version 9.4.This study including all relevant documentation was approved by the Research Ethics Boards at each of the participating sites.A total of 311 consecutive CMV D+/R-kidney recipients within the index period were enrolled across seven Canadian centers (Table 1). There were no screen failures or exclusions. Of these, 103 received a transplant from a living donor (LD) and 208 from a deceased donor (DD); the median age (IQR) at baseline was 58 years and at the first kidney transplant was 55 (42, 64) years; and 69.5% were male and 52.7% were Caucasian. Most participants (68%) lived within 100 km of their transplant center. Primary reasons for kidney failure were diabetes (19.0%), polycystic kidney disease (13.8%), IgA nephropathy (12.5%), other glomerulonephritis (12.2%), or for reasons not specifically defined (26.0%). Most grafts were HLA mismatched (97.7%) with typically two mismatches at HLA-A (44.5%), HLA-B (60.1%), HLA-C (45.4%), HLA-DR (49.6%), HLA-DQ (53.5%) and HLA-DP (47.2%) for those reporting these values. No clinically meaningful differences between those receiving an LD or DD graft were observed with regards to participant baseline characteristics.Most patients received induction with basiliximab (61.4%), ATG (24.4%) or another agent (14.1%), principally alemtuzumab, and 93.9% received mycophenolate mofetil (MMF) or mycophenolic acid (MPA) as maintenance immunosuppression, 87.1% received tacrolimus and 77.2% prednisone (Table 2). Most participants (62.4%) received all 3 maintenance agents, while 33.4% received two and 4.2% only one. All participants received antiviral CMV prophylaxis, principally with valganciclovir (293, 90.2%), started a median of 1 day post-transplant and lasting for a median of 180 days (range: 2-465 days). Most patients received only one course of antiviral therapy (76.2%), though almost one quarter received two (19.0%) or more courses (4.8%). The duration of each course is shown in Table 2. There were no clinically meaningful differences between LD and DD recipients with regards to antiviral prophylaxis. Less than 2% of participants had documented toxicities related to antiviral therapies, of which 28.6% were related to valganciclovir, 14.3% to ganciclovir and 57.1% to other agents (tacrolimus) with antivirals. Outside of myelotoxicity (discussed below), the most common toxicities were neurotoxicity, electrolyte and other toxicities that were 1 No participants related to total of participants post-transplant CMV infection, of whom two and had or more of infection (Table Of these A total of patients antiviral related myelotoxicities principally as leukopenia or neutropenia, with a frequency that was in LD and DD incidence that myelotoxicity was observed within days post-transplant, during the first 3 to at day 100 and by the end of the first year of follow-up 2). The median was 90 days post-transplant, median duration was days and only patients had an NCI-CTCAE severity therapy was reduced in almost of the patients with on or or on of the and antiviral therapy was or in of the (68%) patients on treatment at the time of agents as were in of patients and was in patients during the episode of A episode of myelotoxicity occurred in of these patients at a median of days, with a duration of days, of which had an NCI-CTCAE severity therapy was or incidence of CMV infection following renal incidence of myelotoxicity following total of patients opportunistic infections post-transplant, which were more common in DD than LD recipients (Table incidence that infections were first observed within days post-transplant, to an at days and to approximately by the end of the first with a median of days post-transplant and a median duration of opportunistic infections were recorded in of these of whom had or more for the and or more was days and days with a duration of days and Of the total of opportunistic infection were bacterial, were non-CMV viral infections and were fungal in all were Grade in shown in Table were no differences in the incidence, number of agents or severity of opportunistic infections between patients who or post-transplant CMV infection infection occurred in patients with CMV infection 180 days, than in those CMV infection though was no in duration of opportunistic infections between the two groups total of participants were 103 in the living donor and in the deceased donor Of these admissions, were related to CMV infection or incidence that to by day and to by the end of the first year of The median time to first was 58 days and the median duration was Of these to for a median of of these patients were a of which were related to CMV infection or The median time to was days, and median duration was patients were to ICU for a median of patients were 3 or more of which 3 were for CMV infection or The was a median of days post-transplant, lasting for a median of days and were to ICU for a median of 3 shown in Table the of patients who were not between patients with or CMV infection post-transplant occurred in patients with CMV infection days, than in those CMV infection but was no in duration of hospital stay between the two groups days, the year following all participants a nephrologist a another healthcare an and a general There were no clinically meaningful differences between LD or DD with regards to health care graft rejection occurred in patients overall and DD a median of of these patients received therapy with or patients their graft DD all for reasons other than 1 year 10 patients had DD occurred at a median of days days post-transplant principally to cardiovascular events and other 1 was related to CMV of the 311 patients were alive with a graft by 1 year DD and patient survival were in patients with or post-transplant CMV infection was in participants with post-transplant CMV infections to rejection occurred in the at a median of days days with a median of incidence of opportunistic infection following days in those loss was in patients CMV infection and participants with CMV and participants CMV had by the end of the follow-up and in each group were alive with a graft by 1 year Table study a and comprehensive understanding of current Canadian the clinical outcomes and disease burden of patients at the highest risk of CMV infection as a for It the of current therapy and the patterns of CMV infection in to other events including leukopenia, rejection, infection and the to enable the clinical and economic of strategies to optimize therapy and healthcare resource utilization in this complex of transplantation is a of and Primary CMV infection occurs in of following which the virus by modulating and to facilitate immune may occur in the context of immune dysfunction to disease or No CMV infection with opportunistic immunosuppression, while may follow with another source despite of and of therapy, CMV has been one of the most in transplantation It the clinical course direct (including viral infection and end-organ and indirect consequences including opportunistic bacterial, fungal or other viral by the risk of rejection and graft or events and cardiovascular disease anti-viral treatment has reduced the incidence and severity of CMV disease, leukopenia and other consequences may the so that prophylaxis is to patients at elevated risk defined by CMV age and the of antiviral medication in preventing CMV infection, CMV disease and death with or no treatment prophylaxis and preemptive therapy are the treatment strategies the outcomes in high-risk with opportunistic and graft and patient while the lower costs and drug exposure and lower rates of CMV and of viral The of prophylaxis are in the current study patients received treatment for a median of 180 days, with current CMV infection was delayed a median of but occurred in of patients of whom had CMV disease or end-organ involvement and one quarter had of of these have proposed a in which prophylaxis is by pre-emptive monitoring to identify and infection while this is not challenge most patients have by this which in the current study was up to km from the transplant and duration of CMV treatment are by both costs and adverse of which the most common is leukopenia in of patients The incidence, severity and burden on a combination of including the dose, therapy, renal and which drug and of patients in this study myelotoxicities as leukopenia or occurred within days post-transplant, to almost of all patients by the end of the first year of leukopenia was serious by NCI-CTCAE severity it a reduction or of or antiviral therapy in up to of patients the for CMV infection, of resistant or graft rejection that reduction in treatment is common in kidney transplantation as observed the and effective of is a antiviral agent which the CMV viral the to change current antiviral is to valganciclovir, but leukopenia was reduced by more than and patients treatment to adverse may to drug with tacrolimus and incidence of following immune and therapy have reduced the incidence and impact of opportunistic infection and in kidney transplantation Most infections and hospitalizations occurred in the first 100 days with prior infections occurred in almost of were more common in DD than LD but were to in severity with patients ICU were bacterial, one were viral and were fungal in of all patients were 20% related to or CMV these complications, graft and patient outcomes were graft rejection occurred in only of patients the of these within the first CMV that the between infection and may than the common reduction of in the of the end of of patients alive with a graft with only 1 death to CMV and patient survival were in patients with or post-transplant CMV was in participants with post-transplant CMV infections to rejection occurred in the at a median of days (range: with a median of days (range: in those loss was in patients CMV infection and participants with CMV and participants CMV had by the end of the follow-up and in each group were alive with a graft by 1 year We not yet have for these though are whether in immune suppression and/or viral study has including and which are to the study was conducted a period in which laboratory and clinical management of CMV from a cohort of centers of the transplants in all No CMV infection transplant, within the of the Canadian to in laboratory and clinical may occur from were to these by continuous data to data and identify and values and by data with the we of a in which a broad range of of recipient survival with a kidney graft following transplant by donor of recipient survival with a kidney graft following transplant by CMV and an important in the expression of this virus the consequences of immune suppression and leukopenia is of in this these we may the following CMV infection an important and challenge to clinical for which current strategies are Consequently, within the of and approved clinical guidelines, occurs in the of current the myelotoxicity of current prophylaxis is an important and as it does a of patients and resulting in reduction in of both antiviral agents and immune It is that this response to both the and of CMV infection observed in patients and the of in these the of agents as letermovir myelotoxicity the to optimize strategies for the burden of this the of with key immunosuppressive and the for CMV expression to optimize treatment We that the data obtained in this study will enable to the for effective

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