https://orcid.org/0000-0002-8281-2496
Abstract
Aim
Management of cytomegalovirus (CMV) infection/disease in transplant recipients may be complicated by toxicities and resistance to conventional antivirals, adding to the overall healthcare burden. We characterized treatment patterns, healthcare resource utilization (HCRU), and costs to elucidate the healthcare burden associated with CMV therapies post-transplant.
Materials and methods
A retrospective, longitudinal cohort study of transplant recipients using data from a US commercial insurance claims database (2013–2017) was conducted. Patients with a claim for post-transplant CMV diagnosis and anti-CMV treatment (ganciclovir, valganciclovir, foscarnet, or cidofovir) were identified (Treated CMV cohort) and compared with patients with neither a claim for CMV diagnosis nor anti-CMV treatment (No CMV cohort) for outcomes including HCRU and associated costs. Allogeneic hematopoietic cell transplantation (HCT) or solid organ transplantation (SOT) recipients were analyzed separately. Anti-CMV treatment patterns were assessed in the Treated CMV cohort. Costs were evaluated among subgroups with myelosuppression or nephrotoxicity.
Results
Overall, 412 allogeneic HCT and 899 SOT patients were included in the Treated CMV cohorts, of which 41.7% and 52.5%, respectively, received multiple antiviral courses. Treated CMV cohorts compared with No CMV cohorts had higher mean monthly healthcare visits per patient (allogeneic HCT: 8.83 vs 6.61, SOT: 5.61 vs 4.45) and had an incremental adjusted mean monthly cost per patient differences of $8,157 (allogeneic HCT, p < .004) and $2,182 (SOT, p < .004). Among Treated CMV cohorts, HCRU and costs increased with additional CMV antiviral treatment courses. Mean monthly costs were higher for patients with than without myelosuppression or nephrotoxicity.
Limitations
Results may not be generalizable to patients covered by government insurance or outside the USA.
Conclusions
CMV post-transplant managed with conventional treatment is associated with substantial HCRU and costs. The burden remains particularly high for patients requiring multiple treatment courses for post-transplant CMV or for transplant recipients who develop myelosuppression or nephrotoxicity.
Introduction
Cytomegalovirus (CMV) infection and disease are common complications in hematopoietic cell transplantation (HCT)Citation1,Citation2 and solid organ transplantation (SOT)Citation3 recipients, and are associated with poor clinical outcomes, including graft failure, morbidity, and mortalityCitation4–6. The risk of CMV infection and disease in the transplant population varies depending on several factors, including donor/recipient serostatus, level of immune suppression, and transplant typeCitation7–9.
Current CMV management strategies primarily focus on prophylactic or pre-emptive approaches. The preferred management strategy for SOT recipients at many centers has been prophylaxis, initiated after transplantation and generally maintained for 3–6 months post-transplantation, with longer treatment durations warranted for certain SOT recipients (i.e. lung or high-risk kidney SOT recipients)Citation10. However, CMV disease occurrence is common upon discontinuation of prophylaxis, and extending the antiviral duration to curb late-onset disease can result in serious treatment-associated toxicitiesCitation11,Citation12. Comparatively, CMV in HCT recipients has primarily been managed by pre-emptive therapy (in the era prior to letermovir approval), whereby CMV is regularly monitored by polymerase chain reaction after transplantation to detect early viral replication that prompts antiviral administration in asymptomatic patientsCitation12. This approach can limit antiviral toxicity and reduce rates of late-onset CMV disease, although a defined viral load threshold for initiating therapy has not been establishedCitation11,Citation12.
Treatment strategies for post-transplant recipients can be effective, but the available antiviral agents employed to manage CMV are limited by potential toxicities and the development of treatment resistanceCitation13–20. Conventional antiviral drugs for the treatment of CMV infection in post-transplant recipients include intravenous (IV) ganciclovir, oral valganciclovir, IV foscarnet, and IV cidofovir. The US Food and Drug Administration (FDA) approved letermovir in 2017 for the prophylaxis of CMV reactivation and disease in adult CMV-seropositive recipients of allogeneic HCTCitation21, but it has not been extensively studied for the treatment of active CMV infectionCitation22–24. Current guidelines recommend ganciclovir and valganciclovir for initial treatment of CMV infection in transplant recipientsCitation9,Citation10,Citation12; however, these antivirals are associated with an increased risk of myelosuppression (including neutropenia)Citation25,Citation26, of notable concern among already immunosuppressed transplant recipientsCitation13,Citation14. Foscarnet and cidofovir are recommended as alternative options in patients who are unable to tolerate or fail treatment with ganciclovir or valganciclovir but are associated with an increased risk of nephrotoxicityCitation9,Citation10,Citation12,Citation15,Citation16. Because of such toxicities, patients treated with conventional antivirals require regular hematological and renal monitoringCitation25–27. Resistance or refractoriness to treatment as well as the potential toxicities and development of associated comorbidities noted above are of concern for transplant recipients, who represent a vulnerable patient population. Development of resistance to prior therapy complicates the treatment of CMV infection; up to 14% of transplant recipients have been reported to have CMV infection resistant or refractory to prior antiviral treatmentCitation17–20. Treatment resistance further contributes to CMV-associated morbidity and mortalityCitation16,Citation28,Citation29, and may require the patient to receive multiple antiviral courses or combination therapiesCitation10, adding to the multiple therapies that transplant recipients already receive. Recently, maribavir was approved by the FDA for the treatment of post-transplant CMV, refractory (with or without genotypic resistance) to conventional therapiesCitation30. However, it was not included in the analysis as it was not available at the time of this study.
Given the limitations of conventional CMV antiviral treatments, post-transplant CMV infection may be associated with considerable healthcare resource utilization (HCRU) and costs. Previously published studies have reported an increased economic burden associated with CMV infection and disease following transplantationCitation31–34. However, there remains a paucity of data on the impact of treatment for post-transplant CMV infection and disease on HCRU and costs. Additional real-world information on the sequence of treatments that patients receive for post-transplant CMV infection and disease, as well as the economic implications of multiple courses of treatment for CMV, may provide insights into the current clinical management of CMV infection or disease. Such information may be used to improve patient access to new treatments and potentially to improve outcomes.
The objectives of this real-world US claims database study were to evaluate current treatment patterns, HCRU, and costs associated with the treatment of CMV infection and disease in transplant recipients. Furthermore, healthcare costs were reported among subgroups of patients who had myelosuppression or nephrotoxicity after transplant.
Methods
Study design and population
This was a retrospective, longitudinal cohort study using data from the IQVIA PharMetrics Plus commercial health claims database (IQVIA, Durham, NC, USA; Q1 2013 – Q4 2017, inclusive) that analyzed the HCRU associated costs with conventional anti-CMV treatment (ganciclovir, valganciclovir, foscarnet, or cidofovir) for HCT and SOT recipients. The PharMetrics Plus database includes fully adjudicated claims for privately insured enrollees across the USA. It is de-identified in compliance with the Health Insurance Portability and Accountability Act and institutional review board approval was not required.
Two mutually exclusive samples of patients were identified and analyzed separately based on the procedure code for their first allogeneic HCT or SOT (the index transplant; Figure S1, Tables S1 and S2). Within each of these two samples, mutually exclusive ‘Treated CMV’ and ‘No CMV’ cohorts were identified. Patients in the Treated CMV cohort had ≥1 claim associated with a diagnosis of CMV following the index transplant and ≥1 claim for a CMV antiviral treatment thereafter (ganciclovir, valganciclovir, foscarnet, or cidofovir; the codes used to identify claims for CMV antiviral treatment are shown in Table S3). CMV diagnosis was determined from International Classification of Diseases (ICD) codes (Table S4). The index date for the Treated CMV cohort was defined as the date of initiation of the first CMV antiviral treatment. Patients in the No CMV cohort did not have a claim for diagnosis nor for treatment of CMV. The index date for the No CMV cohort was imputed such that the number of days between the index transplant and the imputed index date was distributed similarly to that of the Treated CMV cohort.
For inclusion in the analyses, patients were required to be aged ≥12 years at the index date and have ≥6 months of continuous enrollment prior to the index date. Patients with a claim for human immunodeficiency virus were excluded.
For both cohorts, the baseline period was the 6-month period prior to the index date, and the observation period was the time between the index date and the end of continuous insurance coverage or the end of data availability, whichever occurred first.
Study data
Patient demographics, relevant clinical characteristics (including Charlson–Quan comorbidity index scoreCitation35) and SOT type or details of the HCT procedure were reported.
CMV treatment patterns and sequencing were defined in terms of the timing of treatment initiation, the antiviral agent used during each treatment course, the proportion of patients who discontinued each treatment course, and the time from start to discontinuation of each course of antiviral.
A treatment course was defined as the period between the initiation of a CMV antiviral therapy and the beginning of a 7-day (valganciclovir, ganciclovir, foscarnet) or 21-day (cidofovir) gap without treatment or the use of another antiviral. A continuous period with overlapping or contiguous ganciclovir and valganciclovir was considered to be a single ganciclovir/valganciclovir course. A period with overlapping or continuous treatment of more than one type of antiviral (except a ganciclovir/valganciclovir course) was defined as a complex course.
HCRU included the interactions between the patient and healthcare services that resulted in a claim being submitted to an insurer. These interactions were categorized based on the care setting in which the service was provided; that is, inpatient stays, emergency room visits, outpatient (clinic) visits, and ‘other’ (other visits included services that were not directly associated with a defined setting, e.g. reimbursement of durable medical equipment, home health agencies, and skilled nursing facilities). HCRU was reported on a per-patient-per-month basis to account for varying lengths of the observation period. Incidence rates (per-patient-per-month) were reported for all-cause healthcare visits, overall and by setting, and for the number of inpatient days.
Monthly healthcare costs were reported on a per-patient basis and included total all-cause healthcare costs and healthcare costs by setting, including pharmacy costs.
Adjusted analyses
All analyses were conducted using SAS 9.4 or SAS Enterprise Guide (SAS Institute Inc, Cary, NC).
Standardized differences were reported to evaluate residual baseline confounding after the inverse probability of treatment weighting (IPTW). For comparative analyses of HCRU and costs between the cohorts, IPTW was applied to the Treated CMV and No CMV cohorts to adjust for confounding. Relevant baseline characteristics that remained imbalanced between the cohorts after IPTW were included in multivariable regressions for comparisons between the cohorts (doubly robust adjustment). Results reported here are for the weighted cohorts unless otherwise specified.
Patient demographics and clinical characteristics after IPTW were reported using descriptive statistics (means, medians, and standard deviations for continuous variables; frequencies and proportions for categorical variables).
Incidence rates of HCRU visits between the Treated CMV and No CMV cohorts were compared using incidence rate ratios (IRRs; negative binomial regression). Mean healthcare costs were compared using mean differences from linear regressions. Confidence intervals (CIs) were estimated using non-parametric bootstrap techniques with 499 replications.
One-year patient subgroup analysis
Owing to the expected heterogeneity in the disease burden of patients closer to the index date, HCRU and costs were compared in a similar manner in a subgroup of patients who were observed for ≥1-year post-index date.
Unadjusted analyses
Treatment patterns
Treatment patterns and the sequence of CMV treatments received during the observation period were analyzed descriptively among patients in the Treated CMV cohorts (unweighted). CMV treatment patterns and sequencing outcomes were stratified by the total number of antiviral treatment course(s) the patients received during the observation period (1 course, 2 courses, ≥3 courses, ≥1 complex course[s]).
HCRU analyses
In the unweighted Treated CMV cohorts, HCRU visits were stratified by the total number of received antiviral treatment courses and descriptively analyzed.
Cost analyses
For patients in the unweighted Treated CMV cohorts, the mean all-cause healthcare costs were also stratified by the total number of treatment courses received.
Costs were also described for a subgroup of patients who had myelosuppression or nephrotoxicity at any point during the observation period (unweighted cohorts). Patients were identified as having myelosuppression and/or nephrotoxicity using ICD codes, procedure codes, and pharmacy claims (Table S5).
Results
Study population
Allogeneic HCT recipients
Of the 4,459 patients identified as having an allogeneic HCT procedure, 412 and 1,659 patients met the inclusion criteria for the Treated CMV and No CMV cohorts, respectively (Figure S2). After IPTW, patient age as of the index date, the proportion of males, and time from transplantation to index date were similar between cohorts (). At baseline, the Treated CMV cohort had a higher Charlson–Quan comorbidity index score than the No CMV cohort (3.4 and 3.1, respectively; standardized difference 13.2%) and had a greater proportion of patients with claims associated with an allogeneic HCT-related malignancy diagnosis (96.3% [397/412] and 90.8% [1,506/1,659], respectively; standardized difference 22.8%), including a greater proportion of patients with a claim associated with acute myeloid leukemia (62.2% [256/412] and 54.9% [911/1,659], respectively; standardized difference 14.8%). There was a higher prevalence of myelosuppression in the Treated CMV (93.0% [383/412]) compared with the No CMV cohort (85.0% [1,410/1,659]; standardized difference 25.1%) during the baseline period. In the Treated CMV cohort, 39.9% of patients had ≥1 claim associated with CMV antivirals prior to the diagnosis of CMV.
The mean (standard deviation [SD]) duration of the observation period for the Treated CMV and No CMV cohorts was 436 (374) and 470 (386) days, respectively.
Table 1. Patient demographics and clinical characteristics in the allogeneic HCT and SOT Treated CMV and No CMV cohorts during the baseline perioda (weighted cohorts).
SOT recipients
A total of 12,683 patients were identified as having received a SOT, with 899 and 2,124 patients meeting inclusion criteria for the Treated CMV and No CMV cohorts, respectively (Figure S2). After IPTW, patient age as of the index date, the proportion of males, time from transplantation to the index date, and Charlson–Quan comorbidity index score was similar between cohorts (). Kidney and liver were the most commonly transplanted organs. Myelosuppression was more prevalent in the Treated CMV (52.2% [469/899]) than the No CMV cohort (45.2% [959/2,124]; standardized difference 14.0%) during the baseline period. In the Treated CMV cohort, 59.1% of patients had ≥1 claim associated with CMV antivirals before CMV diagnosis.
The mean (SD) duration of the observation period was 594 (405) and 429 (357) days for the Treated CMV and No CMV cohorts, respectively.
CMV Treatment patterns
Allogeneic HCT recipients (treated CMV cohort)
During the observation period, the majority of patients in the Treated CMV cohort (58.3% [240/412]) received only 1 course of CMV antiviral treatment, while 41.7% (172/412) received multiple courses. Among the patients who received multiple courses, 75 patients (18.2%) received 2 courses, and 65 patients (15.8%) received ≥3 courses of therapy. At least 1 complex course of therapy was received by 7.8% (32/412) of patients. In the case of patients for whom information on the date of discontinuation was available, the mean time from the start of an antiviral course to discontinuation was 27.0, 29.0, and 27.4 days for courses 1, 2 and 3, respectively.
Across all treatment courses (), valganciclovir was the most common therapy (47%–62% of patients). Foscarnet was received by 10%–21% of patients in each course, with the highest proportion during Course 4. Cidofovir was received by <4% of patients in treatment Courses 1–3. A complex course of therapy was received by 4.1% (17/412), 6.3% (10/160), 2.5% (2/81), 4.8% (2/42), and 9.5% (2/21) of patients in Courses 1–5, respectively.
Figure 1. CMV treatment patterns in the (A) Allogeneic HCT and (B) SOT Treated CMV cohorts. Data are mean (SD) [median]. aA complex course of CMV treatment was defined as a period with overlapping continuous treatment of more than one type of antiviral therapy unless the combination was valganciclovir and ganciclovir. Abbreviations. CMV, cytomegalovirus; HCT, hematopoietic cell transplantation; NA, not applicable; SD, standard deviation; SOT, solid organ transplantation.
![Figure 1. CMV treatment patterns in the (A) Allogeneic HCT and (B) SOT Treated CMV cohorts. Data are mean (SD) [median]. aA complex course of CMV treatment was defined as a period with overlapping continuous treatment of more than one type of antiviral therapy unless the combination was valganciclovir and ganciclovir. Abbreviations. CMV, cytomegalovirus; HCT, hematopoietic cell transplantation; NA, not applicable; SD, standard deviation; SOT, solid organ transplantation.](/cms/asset/dfd3a65e-fb8a-4c31-b31b-d4867db8a9a9/ijme_a_2046388_f0001_b.jpg)
SOT recipients (treated CMV cohort)
Of the 899 patients in the Treated CMV cohort, 427 (47.5%) patients received only 1 course of CMV antiviral treatment, while the majority required more than one treatment (472/899 [52.5%]). Among the patients who required multiple courses, 214 patients (23.8%) received 2 courses, and 250 patients (27.8%) received ≥3 courses of therapy. Less than 1% (8/899) received a complex treatment during the observation period. In the case of patients for whom information on the date of discontinuation was available, the mean time from the start of an antiviral course to discontinuation was 67.3, 57.7, and 58.9 days for courses 1, 2, and 3, respectively.
Among treatments received for Courses 1–5 (), valganciclovir was the most common, used by 84%–92% of patients. Cidofovir and foscarnet were used by <5% of patients in Courses 1–5, and by <3% of patients in each course.
HCRU and costs
Allogeneic HCT recipients
During the observation period, the Treated CMV cohort had a higher incidence rate of all-cause HCRU visits compared with the No CMV cohort (adjusted IRR [aIRR]: 1.25, 95% CI: 1.13–1.38, p < .004; ), and higher mean monthly all-cause HCRU visits per patient (8.83 vs 6.61, respectively). Differences in HCRU between the cohorts were driven by emergency room visits (aIRR: 1.58, 95% CI: 1.16–1.99, p = .004) and inpatient stays (aIRR: 1.50, 95% CI: 1.26–1.77, p = .004). The mean (median) length of inpatient stays was 4.21 (1.44) days for the Treated CMV cohort and 3.96 (0.51) days for the No CMV cohort.
Figure 2. Data in the allogeneic HCT Treated CMV and No CMV cohorts for (A) HCRU (all-cause visits and type of visit) and (B) all-cause mean monthly costs. Panel A: Adjusted IRR represents the incidence rate among the CMV Treated CMV cohort divided by the incidence rate in the No CMV cohort and accounts for inverse probability treatment weighting. Panel B: All-cause mean monthly healthcare costs: adjusted mean difference (95% CI) between the Treated CMV and No CMV cohorts shown in the graph and mean ± SD [median] shown in the table. aIncluded dental or vision care and durable medical equipment. Abbreviations. CI, confidence interval; CMV, cytomegalovirus; HCRU, healthcare resource utilization; HCT, hematopoietic cell transplantation; IRR, incidence rate ratio; SD, standard deviation.
![Figure 2. Data in the allogeneic HCT Treated CMV and No CMV cohorts for (A) HCRU (all-cause visits and type of visit) and (B) all-cause mean monthly costs. Panel A: Adjusted IRR represents the incidence rate among the CMV Treated CMV cohort divided by the incidence rate in the No CMV cohort and accounts for inverse probability treatment weighting. Panel B: All-cause mean monthly healthcare costs: adjusted mean difference (95% CI) between the Treated CMV and No CMV cohorts shown in the graph and mean ± SD [median] shown in the table. aIncluded dental or vision care and durable medical equipment. Abbreviations. CI, confidence interval; CMV, cytomegalovirus; HCRU, healthcare resource utilization; HCT, hematopoietic cell transplantation; IRR, incidence rate ratio; SD, standard deviation.](/cms/asset/4d5ec037-38f8-4c6c-b3d9-a0a90f91840f/ijme_a_2046388_f0002_b.jpg)
During the observation period, patients in the Treated CMV cohort receiving more antiviral courses incurred higher incidences of mean monthly all-cause HCRU visits per patient (), with outpatient visits most common.
Figure 3. (A) HCRU (all-cause visits and type of visit) and (B) all-cause healthcare costs by the number of treatment courses in the allogeneic HCT Treated CMV cohort. Data are reported for the unweighted cohorts and shown as mean ± SD [median]. aIncluded dental or vision care and durable medical equipment. Abbreviations. CMV, cytomegalovirus; HCRU, healthcare resource utilization; HCT, hematopoietic cell transplantation; SD, standard deviation.
![Figure 3. (A) HCRU (all-cause visits and type of visit) and (B) all-cause healthcare costs by the number of treatment courses in the allogeneic HCT Treated CMV cohort. Data are reported for the unweighted cohorts and shown as mean ± SD [median]. aIncluded dental or vision care and durable medical equipment. Abbreviations. CMV, cytomegalovirus; HCRU, healthcare resource utilization; HCT, hematopoietic cell transplantation; SD, standard deviation.](/cms/asset/318dc28d-b0d3-4d48-8634-58242be58e2d/ijme_a_2046388_f0003_b.jpg)
Mean monthly all-cause healthcare costs per patient during the observation period were significantly higher for patients in the Treated CMV than No CMV cohort ($30,431 vs $20,301, respectively, p < .004; adjusted mean difference [AMD]: $8,157, 95% CI: 3,097–13,032; ). The higher overall costs of inpatient stays and outpatient visits were drivers of the total cost differences between the cohorts.
presents the monthly all-cause healthcare costs by the number of treatment courses received. Monthly costs per patient increased as the number of CMV treatment courses increased. The highest mean costs incurred were associated with inpatient stays irrespective of the number of treatment courses received.
One-year patient subgroup analysis
Among allogeneic HCT recipients, 186 patients in the Treated CMV cohort and 834 patients in the No CMV cohort had at least 1 year of follow-up. In this subgroup analysis, the aIRR for all-cause HCRU was 1.39 for the Treated CMV versus No CMV cohort (95% CI: 1.10–1.75, p = .008), driven by outpatient visits (aIRR: 1.36, 95% CI: 1.08–1.68, p = .008). Higher mean monthly costs per patient were also reported for the Treated CMV than No CMV cohort ($13,930 vs $9,400, respectively) in this subgroup; however, cost differences were not as pronounced during the first year compared with those for the whole observation period. Inpatient stays (AMD: $2,635, 95% CI: 1,136–4,619, p < .004) and outpatient visits (AMD: $2,214, 95% CI: 999–3,350, p < .004) were also drivers for the difference in costs between the cohorts in this subgroup analysis.
SOT recipients
During the observation period, the Treated CMV cohort had a higher incidence rate of all-cause HCRU visits compared with the No CMV cohort (aIRR: 1.22, 95% CI: 1.11–1.34, p < .004) and higher mean monthly all-cause HCRU visits per patient (5.61 vs 4.45; ). Drivers of the increased all-cause HCRU for the Treated CMV cohort were the incidence of inpatient stays (aIRR: 1.27, 95% CI: 1.11–1.45, p < .004) and outpatient visits (aIRR: 1.24, 95% CI: 1.13–1.37, p < .004). Mean (median) lengths of inpatient stays were 1.07 (0.20) and 1.83 (0) days for the Treated CMV and No CMV cohorts, respectively.
Figure 4. Data in the SOT Treated CMV and No CMV cohorts for (A) HCRU (all-cause visits and type of visit) and (B) all-cause mean monthly costs. Panel A: Adjusted IRR represents the incidence rate among the CMV Treated CMV cohort divided by the incidence rate in the No CMV cohort and accounts for inverse probability treatment weighting. Panel B: All-cause mean monthly healthcare costs: adjusted mean difference (95% CI) between the Treated CMV and No CMV cohorts shown in the graph and mean ± SD [median] shown in the table. aIncluded dental or vision care and durable medical equipment. Abbreviations. CI, confidence interval; CMV, cytomegalovirus; HCRU, healthcare resource utilization; IRR, incidence rate ratio; SD, standard deviation; SOT, solid organ transplantation.
![Figure 4. Data in the SOT Treated CMV and No CMV cohorts for (A) HCRU (all-cause visits and type of visit) and (B) all-cause mean monthly costs. Panel A: Adjusted IRR represents the incidence rate among the CMV Treated CMV cohort divided by the incidence rate in the No CMV cohort and accounts for inverse probability treatment weighting. Panel B: All-cause mean monthly healthcare costs: adjusted mean difference (95% CI) between the Treated CMV and No CMV cohorts shown in the graph and mean ± SD [median] shown in the table. aIncluded dental or vision care and durable medical equipment. Abbreviations. CI, confidence interval; CMV, cytomegalovirus; HCRU, healthcare resource utilization; IRR, incidence rate ratio; SD, standard deviation; SOT, solid organ transplantation.](/cms/asset/25b050dc-aa11-42d5-88e1-fab7d12687ae/ijme_a_2046388_f0004_b.jpg)
Among patients in the Treated CMV cohort, higher incidences of mean monthly all-cause HCRU visits per patient were incurred by those patients who received additional antiviral courses during the observation period (). Most visits were in the outpatient setting.
Figure 5. (A) HCRU (all-cause and type of visit) and (B) all-cause healthcare costs by the number of treatment courses in the SOT Treated CMV cohort. Data are reported for the unweighted cohorts and shown as mean ± SD [median]. aIncluded dental or vision care and durable medical equipment. Abbreviations. CMV, cytomegalovirus; HCRU, healthcare resource utilization; SOT, solid organ transplantation.
![Figure 5. (A) HCRU (all-cause and type of visit) and (B) all-cause healthcare costs by the number of treatment courses in the SOT Treated CMV cohort. Data are reported for the unweighted cohorts and shown as mean ± SD [median]. aIncluded dental or vision care and durable medical equipment. Abbreviations. CMV, cytomegalovirus; HCRU, healthcare resource utilization; SOT, solid organ transplantation.](/cms/asset/e83fd7ed-6aca-4231-bb00-03d481c5acd3/ijme_a_2046388_f0005_b.jpg)
Mean monthly all-cause healthcare costs per patient were significantly higher for the Treated CMV than No CMV cohort ($8,598 vs $5,788, respectively; p < .004, AMD: $2,182, 95% CI: 1,284–3,145). The Treated CMV cohort incurred higher costs than the No CMV cohort in all settings; however, outpatient visits and pharmacy costs were the drivers of the total cost differences between the two cohorts.
Over the observation period, patients in the Treated CMV cohort who received more antiviral courses incurred higher unweighted monthly all-cause healthcare costs per patient ().
One-year patient subgroup analysis
Among SOT recipients, 596 patients in the Treated CMV cohort and 1,055 patients in the No CMV cohort had at least 1 year of follow-up. In this subgroup analysis, the aIRR for all-cause HCRU was 1.29 for the Treated CMV versus No CMV cohort (95% CI: 1.15–1.44, p < .004), driven by outpatient visits (aIRR: 1.31, 95% CI: 1.16–1.47, p < .004). Higher mean monthly costs per patient were also reported for the Treated CMV than the No CMV cohort ($7,935 vs $3,652, respectively). Inpatient stays (AMD: $1,276, 95% CI: 905–1,603, p < .004) and outpatient visits (AMD: $1,110, 95% CI: 794–1,418, p < .004), as well as pharmacy costs (AMD: $1,252, 95% CI: 1,112–1,400, p < .004), were drivers for the difference between the cohorts in this subgroup analysis.
Healthcare costs in patients who had myelosuppression and nephrotoxicity
Allogeneic HCT recipients
During the observation period, a greater proportion of allogeneic HCT recipients in the Treated CMV than No CMV cohort had myelosuppression (84.7% [349/412] and 63.3% [1,050/1,659], respectively) or had nephrotoxicity (45.9% [189/412] and 31.8% [528/1,659], respectively).
presents the unweighted mean monthly all-cause healthcare costs per patient in these patient subgroups. In the Treated CMV cohort, the mean (SD) costs per patient were $33,870 ($31,168) for patients who had myelosuppression and $20,349 ($26,239) for those who did not. Mean costs were $41,985 ($33,978) and $23,485 ($25,231) for patients in the Treated CMV cohort who did and did not have nephrotoxicity, respectively (). A similar trend was observed for the No CMV cohort (). Inpatient stays were the main driver of costs in the subgroups that had myelosuppression or nephrotoxicity in the Treated CMV cohort (mean [SD] monthly cost of inpatient stays: $18,413 [$25,880], myelosuppression; $24,612 [$27,883], nephrotoxicity).
Figure 6. Mean monthly all-cause healthcare costs per patient in allogeneic HCT and SOT recipients in the overall Treated CMV and No CMV cohorts, and in subgroups of patients who had myelosuppression or nephrotoxicity during the observation period. Data are reported for the unweighted cohorts and shown as mean ± SD [median]. Abbreviations. HCT, hematopoietic cell transplantation; SOT, solid organ transplantation.
![Figure 6. Mean monthly all-cause healthcare costs per patient in allogeneic HCT and SOT recipients in the overall Treated CMV and No CMV cohorts, and in subgroups of patients who had myelosuppression or nephrotoxicity during the observation period. Data are reported for the unweighted cohorts and shown as mean ± SD [median]. Abbreviations. HCT, hematopoietic cell transplantation; SOT, solid organ transplantation.](/cms/asset/839b3b9f-1a2f-4e18-81d8-6ad325847e3c/ijme_a_2046388_f0006_b.jpg)
SOT recipients
During the observation period, a greater proportion of SOT recipients in the Treated CMV than in the No CMV cohort had myelosuppression (56.0% [503/899] and 20.0% [425/2,124], respectively) or nephrotoxicity (45.1% [405/899] and 27.4% [583/2,124], respectively).
In the Treated CMV cohort, unweighted mean (SD) monthly all-cause healthcare costs per patient were $10,617 ($9,790) and $7,612 ($7,983) for patients who did and did not have myelosuppression, respectively. Costs were $12,050 ($10,520) and $7,117 ($7,225) for patients in the Treated CMV cohort who did and did not have nephrotoxicity, respectively (). A similar trend was observed for the No CMV cohort (). Inpatient stays were the main driver of costs in the subgroups that had myelosuppression or nephrotoxicity in the Treated CMV cohort (mean [SD] monthly cost of inpatient stays: $3,492 [$5,773], myelosuppression; $4,803 [$6,825], nephrotoxicity).
Discussion
Current strategies for the treatment of CMV in transplant recipients can be effective, but conventional anti-CMV agents are limited by potential toxicities and the development of CMV refractory (with or without resistance) to treatment, which can negatively affect patient outcomes and result in higher costsCitation31–34. The results of this retrospective US claims database study elucidate the treatment patterns, HCRU, and costs associated with the management of CMV in cohorts of allogeneic HCT or SOT recipients up until 2017.
Our study is among the first to evaluate the treatment and management patterns for post-transplant CMV infection and disease. More than one-third of allogeneic HCT recipients and half of SOT recipients treated for CMV in this study received more than one course of antiviral therapy (41.7% and 52.5%, respectively), highlighting the extent of post-transplant populations requiring multiple treatment courses. Although the reasons for patients requiring multiple courses of treatment were not available in the study database for evaluation, recurrent CMV episodes, lack of response, and treatment-limiting toxicities are commonCitation13–15,Citation36. Treatment with multiple antivirals potentially increases the risk of adverse eventsCitation29,Citation37 and while dose reductions may be used to alleviate side effectsCitation14, suboptimal dosing of antivirals may contribute to the development of CMV resistanceCitation16. Our findings further show that these multiple CMV treatment courses among post-transplant recipients are associated with increased HCRU and costs.
Based on the adjusted mean monthly all-cause healthcare costs observed among patients treated for CMV compared with those without CMV, the additional annual cost is substantial at approximately $97,884 for allogeneic HCT recipients and $26,184 for SOT recipients. Costs were primarily driven by inpatient stays and outpatient visits, which highlights the burden to patients and healthcare systems. Our findings are consistent with prior studies showing that CMV in transplant recipients (predominantly HCT) results in higher HCRU and costsCitation31–33,Citation38–40. Here, we expand upon these prior findings by describing this burden for both SOT and allogeneic HCT populations and showing that HCRU and costs increase for multiple treatment courses, highlighting the significant healthcare and cost burden associated with available CMV treatments in these post-transplant populations. Additionally, the 1-year subgroup analysis reported here highlights the substantial economic burden that occurs shortly after anti-CMV treatment initiation in allogeneic HCT and SOT recipients. Previously published findings support that many HCT patients experience post-transplant complications, including CMV, during the first post-transplant yearCitation31.
As might be expected for the period studied, ganciclovir and/or valganciclovir were the most commonly received antivirals for post-transplant recipients, irrespective of the number of treatment courses. In the allogeneic HCT Treated CMV cohort, foscarnet was more common in later courses of treatment; in the SOT Treated CMV cohort, <3% of patients received cidofovir and foscarnet in each treatment course. This lower percentage among SOT recipients may reflect concerns about the efficacy of combination therapies and toxicities associated with foscarnet and cidofovir as compared with ganciclovir or valganciclovirCitation15,Citation16. Notably, the kidney was the most common transplantation in the SOT Treated CMV cohort and current guidelines recommend ganciclovir or valganciclovir for the treatment of CMV infection in SOT recipients due to the risk of nephrotoxicity associated with foscarnet and cidofovirCitation9. The preferred CMV management strategies in HCT and SOT recipients also differ, due to incidence, risk factors, virologic features, and survival associated with CMV infection in the two transplant populationsCitation41, which may be reflected in these findings.
Myelosuppression or nephrotoxicity are recognized as serious complications of conventional CMV treatments, associated with valganciclovir and ganciclovirCitation25,Citation26 or foscarnet and cidofovirCitation9,Citation10,Citation12,Citation15, respectively. Our study assessed the cost burden for patients with these comorbidities, showing that high overall health costs were incurred by SOT or allogeneic HCT recipients who had these complications. These findings thereby further indicate the adverse economic effects associated with the known limitations of conventional anti-CMV treatments.
Strengths of this study include the use of a large US patient database; however, the data are subject to the inherent limitations associated with the use of a commercial insurance claims database. The enrollee population is generally representative of commercially insured individuals in the USA but may not be representative of patients covered by government insurance. Findings related to HCRU and costs could also be different across geographic regions, including those outside the USA. Furthermore, in this study, claims associated with CMV antivirals prior to diagnosis of CMV may suggest prophylactic use of antivirals; however, patients who received prophylaxis but were never diagnosed with CMV were not included as it would have been impossible to determine if the lack of CMV diagnosis was due to prophylaxis. Thus, the cost of prophylaxis among patients who were never diagnosed with CMV was not included in the current study. Selection bias may have arisen as a result of potential billing inaccuracies and missing data (e.g. miscoding of diagnoses, prescriptions, HCRU, medical services and medications not associated with a claim submitted to an insurer [e.g. over-the-counter medications]); however, these are expected to impact all cohorts equally. This study was also potentially limited by identifying CMV diagnoses based on ICD codes used in claims, which do not distinguish between asymptomatic CMV infection and CMV disease nor indicate disease severity. Although patients may have received CMV treatment and diagnoses for different reasons (including asymptomatic viremia with preemptive therapy or CMV disease with directed therapy), this information is not directly available from the administrative claims database. Further, although non-adherence to oral antiviral therapy has been associated with resistant or refractory CMV diseaseCitation42, reasons for treatment discontinuation or lack of adherence among patients could not be distinguished in this study. Also, the overall study approach and sample selection were defined broadly and therefore did not include the granularity to describe the economic model in smaller subsets (e.g. donor type) of patients. This analysis also included patient populations with different risks, treatment plans, and associated costs. However, they all required a CMV diagnosis before the antiviral treatment, which was a specific group within all transplant recipients who received anti-CMV treatment.
Future research may evaluate the impact on HCRU and costs of newer therapies for the prophylaxis and treatment of post-transplant CMV, such as letermovir after HCT. As letermovir was approved by the FDA for prophylaxis of CMV infection and disease in adult allogeneic HCT recipients in November 2017Citation21, it was outside of the date range of this study. Additionally, identification of cost drivers in the subgroup of patients with myelosuppression and nephrotoxicity will be of interest.
Conclusions
Conventional treatment options for CMV infection or disease in transplant recipients are limited by toxicities and the development of refractory CMV (with or without resistance) to treatment may contribute to poorer outcomes. Findings from this real-world study indicate the high HCRU and costs associated with the management of CMV in the vulnerable immunosuppressed transplant patient population, highlighting the substantial burden of CMV management for these patients. The burden in terms of HCRU and costs is higher among patients who require multiple antiviral courses, while costs are increased in those patients who had myelosuppression and nephrotoxicity. Targeted patient management, adherence support, and education as well as CMV treatment options with improved efficacy and without the toxicities common with conventional agents for patients with CMV, could reduce the high economic and healthcare burden for the vulnerable transplant patient population.
Transparency
Declaration of funding
This research was funded by Takeda Development Center Americas, Inc, Lexington, MA, USA.
Declaration of financial/other interests
WYC, PT-L, and MSD are employees and HCC was an employee (at the time the work was performed) of Analysis Group, Inc, which received funding from Takeda Development Center Americas, Inc to conduct this study. TB and IH are employees of and hold stock/stock options in Takeda Development Center Americas, Inc. RKA has received study funding as a clinical study site investigator for Aicuris, Astellas, Chimerix, Merck & Co., Oxford Immunotec, Qiagen, Regeneron Pharmaceuticals, and Takeda Development Center Americas, Inc, and has acted as an unpaid consultant for Takeda Development Center Americas, Inc.
A reviewer on this manuscript has disclosed that they have received honoraria from Astellas Pharma, Clinigen, Gilead, Janssen, Merck, Novartis, Pfizer. The Deputy Editor in Chief helped with adjudicating the final decision on this paper. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.
Author contributions
WYC, PT-L, HCC, RKA, MSD, IH, and TB contributed to the study design, and review and interpretation of the results. HCC performed statistical programming for the analysis of the results. All authors contributed to the drafting and critical revision of the manuscript, and approved the final text.
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The authors would like to acknowledge the support of Suna Park and Nicolae Done of Analysis Group, Inc for their assistance with data analysis and statistical programming. Under the direction of the authors, Amy Holloway, DPhil, of Caudex, provided medical writing assistance for this manuscript. Editorial assistance was provided by Michael Rowlands, PhD, of Caudex, both funded by Takeda Development Center Americas, Inc.
Data availability statement
The data that support the findings of this study are available from IQVIA (PharMetrics Plus commercial health claims database). Restrictions apply to the availability of these data, which were used under license for this study. Data are available from WYC, PT-L, and MSD of Analysis Group with the permission of IQVIA.
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