Real-World Treatment Patterns of Antiviral Prophylaxis for Cytomegalovirus Among Adult Kidney Transplant Recipients: A Linked USRDS-Medicare Database Study

Limited data exist on cytomegalovirus (CMV) antiviral treatment patterns among kidney transplant recipients (KTRs). Using United States Renal Database System registry data and Medicare claims (1 January 2011–31 December 2017), we examined CMV antiviral use in 20,601 KTRs who received their first KT from 2011 to 2016. Three-quarters of KTRs started CMV prophylaxis (86.9% of high-, 83.6% of intermediate-, and 31.7% of low-risk KTRs). Median time to prophylaxis discontinuation was 121, 90, and 90 days for high-, intermediate-, and low-risk KTRs, respectively. Factors associated with receiving CMV prophylaxis were high-risk status, diabetes, receipt of a well-functioning kidney graft, greater time on dialysis before KT, panel reactive antibodies ≥80%, and use of antithymocyte globulin, alemtuzumab, and tacrolimus. KTRs were more likely to discontinue CMV prophylaxis if they developed leukopenia/neutropenia, had liver disease, or had a deceased donor. These findings suggest that adherence to the recommended duration of CMV-prophylaxis for high and intermediate-risk patients is suboptimal, and CMV prophylaxis is overused in low-risk patients.


INTRODUCTION
Cytomegalovirus (CMV) is the most common opportunistic infection in kidney transplant recipients (KTRs) (1,2).In the absence of prevention, 20%-60% of KTRs develop CMV infection/disease.CMV infection and its manifestations increase the risk of rejection, graft loss, and mortality (1,3).Previous research has shown that the use of CMV antiviral agents, including (val)ganciclovir, is associated with a reduced risk of CMV infection/disease (3)(4)(5)(6)(7).Prophylactic use of these antivirals not only lowers the risk of CMV infection/disease, but also mitigates the negative impact of CMV on graft and survival outcomes (3)(4)(5)(6)(7).However, currently available CMV antiviral agents may lead to adverse outcomes such as myelosuppression from (val)ganciclovir or nephrotoxicity from foscarnet, which may require modifications to antiviral or immunosuppressive therapy regimens that can also adversely affect graft and survival outcomes (3,5,7,8).
CMV serostatus is a key determinant of CMV infection/disease risk.CMV seronegative KTRs (R-) who received a graft from a CMV seropositive donor (D+) are at the greatest risk for CMV infection/disease, followed by CMV seropositive (R+) KTRs regardless of donor serostatus (D±), who are at intermediate risk, and CMV seronegative KTRs who receive a graft from a CMV seronegative donor (D-/R-), who are at lowest risk of CMV infection/disease (9).CMV prevention is prioritized for high-risk KTRs, leading to a recommended 200 days of prophylaxis, while efficacy and safety are balanced for intermediate-risk KTRs, leading to a recommended duration of 100 days.CMV prophylaxis is not recommended for low-risk KTRs.The standard valganciclovir daily dose of 900 mg can be lowered to 450 mg to reduce the risk of myelosuppression if antiviral toxicities are a concern, but this strategy may be suboptimal (10).
While preemptive therapy can be substituted for prophylaxis if the KTR has the logistical support necessary for monitoring, a recent systematic review of post-transplant CMV preventive strategies for nearly 70,000 KTRs found that prophylaxis was the most common approach for high-risk transplants, preemptive therapy was the most common approach for intermediate-risk transplants, and ganciclovir or valganciclovir were identified as the most commonly used medications regardless of CMV risk (3).However, the majority of reported studies are limited to examining a single center, or are outdated due to updated guidelines supporting a longer duration of CMV prophylaxis consistent with results from the IMPACT clinical trial (11).Additionally, few studies have published CMV prophylaxis patterns among KTRs using large-scale national-level databases in the United States (US), leaving a gap in real-world evidence regarding the characteristics and determinants of CMV prophylaxis patterns among adult KTRs.Therefore, we conducted this study to determine patterns of CMV prophylaxis use and identify factors associated with use and duration of CMV prophylaxis.

Data Source
We used files from the US Renal Data System (USRDS) linked to Medicare claims between 1 January 2011 and 31 December 2017 (12).The USRDS is a national registry that collects treatment and outcomes data from individuals with chronic kidney disease and endstage renal disease (ESRD) in the US.The USRDS-Medicare database is considered the most complete source of information on the use of healthcare services by KTRs in the US, because ESRD is a qualifying condition for Medicare coverage and the registry includes all individuals who require maintenance dialysis.The USRDS standard analysis files contain data on person-level clinical and demographic characteristics, kidney transplant (KT) information from the United Network of Organ Sharing (UNOS), and death.The standard USRDS files can be linked to Medicare Institutional (Part A), Physician/ Supplier (Part B), and Prescription Drug (Part D) claims.This study was approved by the New England Institutional Review Board on 9 September 2020 (study number 1289813) and was conducted in accordance with the International Society for Pharmacoepidemiology Guidelines for Good Pharmacoepidemiology Practices, Revision 3, the principles of the Declaration of Helsinki, and all applicable federal, state, and local laws, rules, and regulations.

Study Design and Sample
We performed a retrospective, observational cohort analysis of individuals who were at least 18 years of age at the time of their first KT that occurred between 1 June 2011 and 31 December 2016.The claims-derived date of their first KT was used as the KTRs' index dates.Included KTRs had to have at least one medical procedure claim for KT in the Medicare claims data within 15 days of the registry-based date of the KT; at least 6 months of continuous Medicare Parts A, B, and D coverage prior to their index date; and at least 12 months of continuous Medicare Parts A, B, and D coverage post-index date or continuous Medicare Part A, Part B, and Part D up to date of death if death occurred within 1 year of transplant.KT was identified by the International Classification of Diseases, Clinical Modification diagnosis codes 55.69 (ninth revision) and 0TY00Z0, 0TY00Z1, 0TY00Z2, 0TY10Z0, 0TY10Z1, and 0TY10Z2 (10th revision) in the Medicare Claims data.Once all KTRs who met inclusion criteria were identified, exclusion criteria were applied to identify our final cohort (Figure 1).Exclusion criteria included evidence of HIV/AIDS or pregnancy in claims data, missing CMV or UNOS information at index date, claim for CMV during the baseline period, died on day of KT, CMV serostatus missing, and valganciclovir dose missing or exceeded 1,800 mg/day.

Definitions of CMV Prophylaxis and Duration
We defined CMV prophylactic therapy as use of ganciclovir or valganciclovir within 28 days after the KT index date.CMV antiviral therapies were identified in Part D Medicare claims using National Drug Codes for ganciclovir and valganciclovir, or Parts A or B Medicare claims using Healthcare Common Procedure Coding System (HCPCS) or Current Procedural Terminology (CPT) codes for administration of those agents.To calculate duration of CMV prophylaxis, we first identified the fill date and the days' supply and then estimated the run-out date for each CMV antiviral prescription.We defined the index   prescription as the first CMV antiviral medication within 28 days after the KT.Fill gaps were then calculated, where a fill gap was the difference between run-out date and the next fill date for the CMV prophylactic antiviral being used.Finally, we defined the last prophylaxis prescription by the first occurrence of a fill gap of ≥15 days after the index prescription.Duration was the difference between the last prophylaxis prescription run-out date and the index prescription fill date.

Valganciclovir Daily Dose
We estimated the total daily dose (TDD) for each identified valganciclovir prescription by multiplying the strength of the prescription by the number of tablets dispensed, divided by the number of days supplied (e.g., 60 tablets of valganciclovir 450 mg dispensed for 30 days equals a TDD of 900 mg).
Once calculated for each prescription, an average TDD for CMV prophylaxis was calculated for each KTR and used to classify KTRs to a valganciclovir daily dose category (450 mg, 900 mg, or other).

Definitions of Leukopenia and Neutropenia
We created time-varying covariates to capture when KTRs developed leukopenia and/or neutropenia on or after their transplant dates.These time-varying covariates were defined using diagnosis codes present during hospitalizations and were equal to "no" until the date of their first relevant diagnosis code for each condition, after which point they were set equal to "yes." Other KTR Characteristics

Statistical Analysis
Summary statistics were used to describe the KTRs and their CMV prophylaxis patterns.Comparisons between groups were performed using the F-test from analysis of variance and the chisquare test for continuous and categorical variables, respectively.All analyses were stratified by CMV risk associated with the donor/recipient serostatus.Results for cells containing fewer than 11 KTRs have been suppressed (i.e., reported as "<11") as required by the USRDS data use agreement.We generated Kaplan-Meier (KM) curves to visualize time to prophylaxis discontinuation and the log-rank test to assess differences between those curves.Multivariable logistic and Cox proportional hazard (PH) regression models were used to estimate the adjusted associations between KTRs' demographic and clinical characteristics and the probabilities of starting and discontinuing, respectively, their CMV prophylaxis.Regression models were estimated for all KTRs while adjusting for risk group and separately by risk group, and results were reported as odds and hazard ratios for the logistic and Cox PH models, respectively, along with 95% confidence intervals and twosided p-values.The logistic and PH Cox regression models included the same core set of covariates, which was selected based on the literature; the PH Cox models also included two time-varying covariates capturing post-KT occurrence of leukopenia and neutropenia.When variables were missing values, we applied the following imputation strategies.For continuous variables such as time on dialysis and time on the transplant waiting list, we replaced the missing values with the risk-group-specific means.For categorical variables such as cold ischemia time, PRA, and HLA A B match, we replaced the missing values with the risk group-specific modal value.
Missing values for categorical cold ischemia time and donor creatinine level were imputed after imputing the source continuous variables.

Baseline Characteristics
We identified 67,838 individuals who received their first KT from 2011 to 2016, of whom 20,601 satisfied all inclusion and exclusion criteria (Figure 1).

Use and Factors Associated With the Use of CMV Antiviral Prophylaxis
Table 2 displays, and compares across risk groups, the CMV prophylaxis characteristics of KTRs who started CMV prophylaxis.Slightly over three-quarters (77.0%) of KTRs started CMV prophylaxis (86.9% of high-, 83.6% of intermediate-, and 31.7% of low-risk KTRs).Overall, 59.7% and 32.5% of KTRs who started CMV prophylaxis used valganciclovir 450 mg and 900 mg, respectively, while 7.8% used other doses of valganciclovir; no patients used ganciclovir.Overall, KTRs who started prophylaxis did so, on average, 4.2 days after receiving their KTs; time to starting prophylaxis did not vary substantially across risk groups (4.1-4.5 days).Table 3 displays the results of the logistic regression models for use of CMV prophylaxis (descriptive statistics stratified by CMV prophylaxis status within risk group are available in Supplementary Table 1).In general, CMV risk status was the factor most strongly associated with the use of CMV prophylaxis.KTRs who were younger, female, African American or of other races, resided in the Northeast, as well as those whose donor creatinine levels were >1.5 mg/dL, who spent more time on dialysis prior to KT, had PRA ≥80%, and who used ATG, and alemtuzumab were more likely to receive CMV prophylaxis (all and intermediate-risk KTRs).KTRs whose kidney graft experienced cold ischemia time <24 h, used basiliximab, AZA, everolimus, or cyclosporine, or prednisone and/or methylprednisolone were less likely to receive CMV prophylaxis (all and intermediate-risk KTRs).Additionally, highrisk KTRs who had PRA ≥80% were more likely to receive CMV prophylaxis; whereas those with comorbid diabetes, and who used AZA, everolimus, or cyclosporine, MMF or other maintenance immunosuppressive agents were less likely to receive CMV prophylaxis.Low-risk KTRs who were female, resided in the South, and used ATG and alemtuzumab or other immunosuppression as induction immunosuppressive agents were more likely to receive CMV prophylaxis.prophylaxis did so for ≥200 days (23.4% and 12.7% of high-risk KTRs who used valganciclovir 450 mg and 900 mg, respectively, did so for ≥200 days) and more than half (55.8%) of high-risk KTRs used CMV prophylaxis for ≥100 days (64.0% and 44.8% of high-risk KTRs who used valganciclovir 450 mg and 900 mg, respectively, did so for ≥100 days).Over one-third (36.5%) of intermediate-risk KTRs used CMV prophylaxis for ≥100 days (39.4% and 23.3% of intermediaterisk KTRs who used valganciclovir 450 mg and 900 mg, respectively, did so for ≥100 days).

Duration of Prophylaxis and Factors Associated With Risk of CMV Prophylaxis Discontinuation
Table 4 displays the results of the PH Cox regression models for time to CMV prophylaxis discontinuation.We found that, regardless of risk group, KTRs who resided in the South and who developed leukopenia were more likely to discontinue CMV prophylaxis; all KTRs, as well as intermediate-risk group KTRs who developed neutropenia were also more likely to discontinue.Additionally, overall and intermediate-risk KTRs with comorbid liver disease, who experienced a longer wait time, lived in the Midwest, or received MMF or tacrolimus were more likely to discontinue CMV prophylaxis.Among the overall, high-, and intermediate-risk KTRs, those who were younger, received kidney grafts from deceased donors, or lived in the West or other US territories were  more likely to discontinue prophylaxis.Finally, overall, intermediate-, and low-risk KTRs who identified as African American were more likely to discontinue CMV prophylaxis, as were overall and intermediate-risk KTRs of other races.
discharge without a prior diagnosis of CMV during the index transplant (28).Therefore, it was highly unlikely that these agents were used as pre-emptive therapy.Finally, because we only included Medicare Part D enrollees in our sample, our findings may not be generalizable to commercial insured or Medicare advantage enrollees and individuals who reside outside the United States.However, despite these limitations, our study has many strengths.Our study used a large and detailed database containing KT registry data linked to Medicare claims that allowed us to analyze a broad number of donor and recipient clinical characteristics.Furthermore, we were able to accurately capture medication use patterns by limiting the sample to Medicare Part D-covered beneficiaries.Our findings contribute to the literature by documenting improvements in adherence to guideline recommendations for managing CMV in KTRs.

CONCLUSION
This study provides the most up-to-date information on national-level CMV prophylaxis among KTRs in the US.Most, but not all, high-and intermediate-risk KTRs received CMV prophylaxis, and virtually all KTRs who started prophylaxis used valganciclovir.However, our findings also highlight that adherence to the recommended duration of CMV prophylaxis is suboptimal.Furthermore, this is the first study of a very large sample of KTRs to confirm the association between development of leukopenia and neutropenia and subsequent risk of CMV prophylaxis discontinuation.

Figure 2
Figure2displays the KM curves for time to prophylaxis discontinuation.The median time to prophylaxis discontinuation (i.e., prophylaxis duration), derived from the KM curves, for the high-risk group of KTRs was longer (121 days) than for intermediate-(90 days) and low-risk (90 days) KTRs.Regardless of type of antiviral agent used, 10.9% of KTRs who used CMV prophylaxis did so for ≥200 days (23.4% and 12.7% of high-risk KTRs who used valganciclovir 450 mg and 900 mg, respectively, did so for ≥200 days) and more than half (55.8%) of high-risk KTRs used CMV prophylaxis for ≥100 days (64.0% and 44.8% of high-risk KTRs who used valganciclovir 450 mg and 900 mg, respectively, did so for ≥100 days).Over one-third (36.5%) of intermediate-risk KTRs used CMV prophylaxis for ≥100 days (39.4% and 23.3% of intermediaterisk KTRs who used valganciclovir 450 mg and 900 mg, respectively, did so for ≥100 days).Table4displays the results of the PH Cox regression models for time to CMV prophylaxis discontinuation.We found that, regardless of risk group, KTRs who resided in the South and who developed leukopenia were more likely to discontinue CMV prophylaxis; all KTRs, as well as intermediate-risk group KTRs who developed neutropenia were also more likely to discontinue.Additionally, overall and intermediate-risk KTRs with comorbid liver disease, who experienced a longer wait time, lived in the Midwest, or received MMF or tacrolimus were more likely to discontinue CMV prophylaxis.Among the overall, high-, and intermediate-risk KTRs, those who were younger, received kidney grafts from deceased donors, or lived in the West or other US territories were

TABLE 1 |
Baseline demographic, clinical, and medication-related characteristics of adult KTRs.
a p-values are compared across patients by donor/recipient serostatus group using t-tests or analysis of variance (ANOVA) for continuous variables or chi-square tests for categorical variables.b Other includes American Indian, Alaska Native, Native Hawaiian, Pacific Islander, multiracial, other, and unknown.

Table 1
summarizes the characteristics of our sample.Most (69.2%)KTRs were at intermediate risk of CMV infection, while 17.0% and 13.8% were at high and low risk, respectively.KTRs were, on average, 53.2 years of age at their initial KT.Most KTRs were male (60.1%) and White (60.0%);one-third were African American.
proportions of KTRs received their kidney grafts from a deceased donor (81.5%) and were positive for Epstein-Barr virus (82.0%).Most donor kidneys experienced <24 h of cold ischemia time (81.6%) and were well-functioning (donor creatinine clearance ≤1.5 mg/dL).KTRs were less likely to have had three or more HLA A B matches than other KTRs.Intermediaterisk KTRs were slightly older and more likely to be female, African American or Asian, Hispanic, reside in the South or West regions, have diabetes or hypertensive nephrosclerosis as the primary cause of ESRD,

TABLE 2 |
Characteristics of CMV prophylaxis among adults undergoing first kidney transplant by serostatus.

TABLE 3 |
Logistic regression for probability of starting CMV prophylaxis among adults undergoing a first kidney transplant.

TABLE 4 |
Cox proportional hazard regression for time to CMV prophylaxis discontinuation among adults undergoing a first kidney transplant.