Abstract
Background:
Ganciclovir (GCV) and foscarnet (FOS) are the most commonly used antivirals for preemptive treatment of cytomegalovirus (CMV) viremia in recipients of allogeneic hematopoietic cell transplantation (alloHCT). The current literature indicates similar efficacy between these agents. Thus, the primary consideration for choice of initial anti-CMV treatment is the safety profile, time period after alloHCT and concern of myelosuppression or renal dysfuction.
Methods:
Herein, we retrospectively reviewed medical records of 124 alloHCT recipients who received GCV or FOS between April 27, 2014 and December 31, 2015 during the first year post-transplant. Health care resource use included drug, hospitalization, home health, dialysis, and growth factor costs.
Results:
Total duration of therapy was longer in the GCV group (37 days vs. 28 days, p=0.21) but hospitalization days were similar (9 days) in both groups. The total treatment cost was significantly lower in the GCV group ($38,100 vs. $59,400, p<0.05).
Conclusion:
Preemptive anti-CMV therapy is associated with major health care resource costs, which were greater in patients who required FOS than those who were treated with GCV.
Keywords: cytomegalovirus, ganciclovir, foscarnet, hematopoietic cell transplant, drug costs
INTRODUCTION
Cytomegalovirus (CMV) infection is a common complication of allogeneic hematopoietic cell transplantation (alloHCT) that can result in end-organ disease.1,2 Based on results of a large study sponsored by the Center of International Blood and Marrow Transplant Research, CMV viremia is associated with increased rates of non-relapse mortality (NRM) in alloHCT recipients.3,4 Prior to the recent approval of letermovir, preemptive therapy (PET) with CMV anti-viral agents has been the standard of care.5 PET involves surveillance and institution of anti-CMV antiviral agent therapy upon detection of CMV in blood (or plasma).6,7
Current treatment options for CMV infection in recipients of hematopoietic cell transplant are limited to ganciclovir (GCV), foscarnet (FOS), and cidofovir; with GCV being the first-line treatment and FOS and cidofovir being the second and third line, respectively. GCV therapy is known to cause neutropenia and thrombocytopenia which can be problematic in the early phase of alloHCT.6,7 Valganciclovir is an oral pro-drug of ganciclovir that is rapidly converted to ganciclovir upon administration. Valganciclovir has high bioavailability with side effect profile similar to ganciclovir. This drug can be considered in patients who are able to tolerate oral medications and do not have any underlying conditions (e.g., GVHD of the gut with diarrhea, mucositis, vomiting) that may affect the drug absorption. FOS has been increasingly used in patients with cytopenia, delayed engraftment, poor graft function and slow response to GCV. The most serious side effect of FOS and cidofovir is nephrotoxicity, which may lead to renal failure or electrolyte abnormalities.6,7
While GCV and FOS are used as PET for CMV infection, there are very few studies comparing the effectiveness of one agent over another.8,9 In one randomized study, Reusser et al. compared GCV and FOS as preemptive therapy for CMV viremia after hematopoietic cell transplantation with the primary efficacy endpoint being CMV end-organ disease occurrence or death from any cause within 180 days of alloHCT. Results of this study suggested similar efficacy for GCV and FOS in treating CMV viremia. However, fewer patients in the FOS group (4%) developed severe neutropenia requiring discontinuation of therapy compared to the GCV group (11%).9 Similar results were reported in another study by Moretti et al, with a slightly higher failure rate to control CMV antigenemia in patients receiving GCV.8
Given the similar efficacy between GCV and FOS for CMV viremia treatment, the primary consideration to use one drug over another in alloHCT patient is mainly dependent on the toxicity profile of the drug in relation to the engraftment status, allograft function, renal function, tolerability and to a lesser extent on the treatment costs. We performed this pilot study due to the paucity of literature surrounding cost differences with the use of FOS or GCV for CMV infection. However, recently a multicenter study detailing cost of PET in CMV infection has been published that shows significant cost burden with PET.10 Another recent large retrospective database study investigating the clinical and economic burden of CMV management post alloHCT in Japan reported that CMV episodes post-HCT are associated with significantly increased healthcare resource utilization.11 Moreover, with the possibility of changing drug costs over time, we limited this study to a recent cohort of patients undergoing alloHCT. The primary objective of this study was to compare health care resource utilization (HCRU) between GCV and FOS in the treatment of CMV viremia. Secondary objectives were to evaluate differences in clinical outcomes (CMV viral load kinetics, end-organ disease, and mortality) along with side effects and complications arising from the utilization of either agent.
PATIENTS AND METHODS
Study Design
In this single-center, Institutional Review Board approved retrospective study, medical records of 124 patients who underwent alloHCT at the City of Hope between April 27, 2014 and December 31, 2015 and received GCV or FOS within the first 365 days after alloHCT were reviewed. Variables that could impact the health care resource utilization as a result of anti-viral choice were evaluated (i.e., use of growth factors and dialysis, and high costs of drug / hospitalization as a direct adverse effect of the anti-viral medication). Inclusion criteria were administration of either GCV/valganciclovir or FOS for at least 5 days after a positive CMV PCR. Exclusion criteria were the presence of CMV end-organ disease prior to or with the first episode of viremia or the use of cidofovir. GCV is the drug of choice at our institution for pre-emptive treatment of CMV viremia, and FOS is used only in patients who have neutropenia, do not respond to GCV, or develop GCV resistance. The study design and method of patient selection are outlined in Figure 1. Patients were grouped into the GCV or FOS populations depending on the agent that was initially used.
Figure 1.
Patient selection diagram.
Data Collection
Patient’s age, gender, underlying malignancy, type of transplant, conditioning regimen, CMV serostatus, and incidence of graft-versus-host disease (GVHD) were collected. Health care resource use included drug costs, hospitalization days, growth factor utilization, home infusion visits, and dialysis. Efficacy endpoints were CMV viral loads from days 0 to 21 of pre-emptive treatment for CMV reactivation, recurrence of viremia, development of CMV end-organ disease, and mortality. Efficacy measures (recurrence of CMV viremia, CMV end-organ disease, death and death with active CMV viremia) were collected at one year following the initiation of treatment. Safety endpoints included elevated serum creatinine ≥ 1.3 mg/dL, doubling of serum creatinine above baseline, and reductions in white blood cell count by at least 50% from baseline at any time point during therapy.
Definitions
CMV viral load thresholds for initiating PET were defined as follows: 1) CMV PCR ≥ 1,250 IU/mL (>500 genomic copies/ml with a conversion factor of one genomic copy/ml = 2.5 IU/ml) for haploidentical or cord blood transplants, or 2) CMV PCR ≥ 3,750 IU/mL (>1500 genomic copies/ml) for all other alloHCT, or 3) a rising CMV PCR in high risk patients. High risk criteria included but were not limited to the following: cord blood HCT, haploidentical HCT, acute GVHD grade II-IV, chronic GVHD, high dose corticosteroid therapy (≥1 mg/kg daily), prior anti-thymocyte globulin use, use of clofarabine, lymphopenia, or use of a T-cell depleting regimen.
Cost Analysis
Drug costs were calculated using 2017 wholesale acquisition costs (WAC). Other health care costs were calculated using reference costs from national databases.12–14 The cost of hospitalization adjusted expenses per inpatient day for a non-profit hospital in California in 2017 was $3,752.12 To obtain hospitalization costs, this number was multiplied by the number of hospitalization days that each patient was admitted for pre-emptive treatment of CMV viremia. Wholesale acquisition costs for different medications are as follows: GCV 500 mg vial-$97.27 (generic), FOS 6 gram vial-$431.90, valganciclovir 450 mg tablet (generic)-$51.52, and filgrastim 300 mcg vial-$305.96. Study agent costs were calculated by applying the appropriate weight-based dosing for each agent with the individual weight of each patient. Per institutional policy, the dosing for ganciclovir is 5 mg/kg/dose and for foscarnet is 90 mg/kg/dose with the dosing frequency of induction being every 12 hours and maintenance being every 24 hours using actual body weight. Treatment costs accounted for the duration of induction and maintenance therapy along with the duration of oral therapy if patients were transitioned from intravenous GCV or FOS to valganciclovir. Filgrastim costs were calculated from the total number of doses that each patient received and each dose was assumed to be 5 mcg/kg. The cost of home infusion therapy was calculated as $200 per day, and the hemodialysis per person per year cost was calculated as $87,945, based on the Medicare database.13,14 To obtain per patient costs for home infusion and hemodialysis, the total number of days was averaged out among all of the patients in each group.
Data Analysis
The Fisher’s exact and chi-squared tests were used for dichotomous and categorical variables. Continuous variables were analyzed using the student’s t-test. P-values of <0.05 were considered statistically significant. The Fisher’s exact and chi-squared tests were performed using an online calculator (Social Science Statistics), and the student’s t-test was performed using Microsoft Excel.
RESULTS
Patient Characteristics
Of 124 screened patients, 100 patients were identified with CMV viremia (Figure 1). Sixty-four patients met the inclusion criteria and were grouped into the GCV or FOS populations depending on the agent that was initially used. Fifteen of the 64 patients (23%) were initially started on one agent and later switched to the other. Of the 36 patients that were excluded from the study, nine patients had suspected CMV end-organ disease at baseline, three patients received concurrent cidofovir, and one patient was excluded due to the absence of data regarding their treatment or follow-up. The remainder of the excluded patients either did not meet criteria to start pre-emptive treatment for CMV viremia or were not on antiviral therapy for a sufficient amount of time.
Baseline demographic characteristics between the GCV (n=52) and FOS (n=12) groups are described in Table 1. Most of the baseline characteristics were similar between both groups. However, patients in the GCV group underwent more haploidentical transplants, and patients in the FOS group underwent more cord blood transplants. Majority of patients in both groups were male and developed acute or chronic GVHD. Leukemia was the most common indication for alloHCT. Approximately 50% of patients received myeloablative conditioning, which consisted of regimens with busulfan, cyclophosphamide, etoposide, and/or total body irradiation. Of the 52 patients in the GCV group, 13 patients (25%) were later switched from GCV to FOS. More than 50% of the these patients (n=8) were switched due to the worsening of CMV viremia while on GCV. Four patients (30%) were switched because of neutropenia and other side effects. Twelve patients in the GCV group (23%) were eventually transitioned to oral valganciclovir. Of the 12 patients in the FOS group, 2 patients (17%) were later switched to GCV due to renal side effects. Two patients in the FOS group (16.7%) were eventually transitioned to oral valganciclovir.
Table 1:
Baseline Demographics
| Ganciclovir (n=52) | Foscarnet (n=12) | P value | |
|---|---|---|---|
| Median Age | 55.5 (9 to 73) | 53 (22 to 66) | 0.63 |
| Male | 33 (63%) | 10 (83%) | 0.31 |
| Underlying Condition | 0.27 | ||
| Leukemias | 34 (65%) | 5 (42%) | |
| Myelodysplastic Syndrome | 5 (10%) | 1 (8%) | |
| Lymphomas | 4 (8%) | 3 (25%) | |
| Multiple Myeloma | 1 (2%) | 0 (0%) | |
| Other | 8 (15%) | 3 (25%) | |
| Type of Transplant | 0.21 | ||
| Matched Related Donor | 7 (14%) | 4 (33%) | |
| Matched Unrelated Donor | 21 (40%) | 3 (25%) | |
| Haploidentical | 17 (32%) | 2 (17%) | |
| Cord Blood | 7 (14%) | 3 (25%) | |
| Myeloablative Conditioning | 23 (44%) | 7 (58%) | 0.52 |
| CMV Serostatus (Donor/Recipient) | 1.00 | ||
| +/+ | 28 (54%) | 6 (50%) | |
| +/− | 0 (0%) | 0 (0%) | |
| −/+ | 24 (46%) | 5 (42%) | |
| −/− | 0 (0%) | 0 (0%) | |
| Acute GVHD | 31 (60%) | 7 (58%) | 1.00 |
| Chronic GVHD | 8 (15%) | 1 (8%) | 1.00 |
| White Blood Cell Count (k/uL) | 5.2 (<0.1 to 15.6) | 1.8 (<0.1 to 3.9) | <0.05 |
| Absolute Neutrophil Count (k/uL) | 3.3 (<0.1 to 11.9) | 1.1 (<0.1 to 3.5) | <0.05 |
Clinical Outcomes
Clinical outcome measures are outlined in Table 2 and Figure 2. With respect to the magnitude and clearance of CMV viremia by day 21 following the initiation of pre-emptive treatment, no difference was observed between GCV- and FOS-treated patients. There were no statistically significant differences between GCV and FOS groups in the clearance of CMV viremia, CMV end-organ disease, or death at 1 year after the initiation of either CMV anti-viral agent.
Table 2:
CMV Outcomes at 1 Year Follow-Up
| Ganciclovir (n=52) | Foscarnet (n=12) | P value | |
|---|---|---|---|
| Recurrence of CMV Viremia | 9 (16%) | 4 (33%) | 0.24 |
| CMV Disease | 2 (4%) | 0 (0%) | 1.00 |
| Death | 16 (28%) | 5 (42%) | 0.50 |
| Death with Positive CMV Viremia | 7 (13%) | 1 (8%) | 1.00 |
Figure 2.
CMV viral load kinetics per ganciclovir or foscarnet administration in 21 days.
Safety Outcomes
Safety outcome measures are outlined in Table 3 and Figure 3. Serum creatinine elevations were observed more frequently in the FOS group, but the difference was not statistically significant. Fourteen patients (27%) from the GCV group and six patients (50%) from the FOS group developed serum creatinine ≥ 1.3 mg/dL (p = 0.17). A similar trend was observed with a doubling of serum creatinine at any point in therapy: 6 patients (12%) vs. 3 patients (25%) (p = 0.35). The frequency (25% vs 0%, respectively, p<0.05) and duration of dialysis reflected FOS’s higher propensity to cause renal impairment. As expected, a higher proportion of patients in the GCV group experienced reductions in white blood cell count: 33 patients (63%) vs. 6 patients (50%); p=0.51, which was not statistically significant (Figure 3b). Not surprisingly, since GCV was avoided during periods of low WBC, the percentage of patients receiving growth factor support and the median number of filgrastim doses administered during PET for CMV were greater in the FOS group (data not shown), although these differences were also not statistically significant.
Table 3:
Adverse Effects Leading to Therapy Adjustment
| Ganciclovir (n=52) | Foscarnet (n=12) | P Value | |
|---|---|---|---|
| Filgrastim Use | |||
| # of Patients (%) | 28 (54%) | 9 (75%) | 0.21 |
| Median # of Doses (Range) | 1 (0 to 23) | 4 (0 to 25) | 0.27 |
| Dialysis | |||
| # of Patients (%) | 0 (0%) | 3 (25%) | <0.05 |
| Median # of Days (Range) | - | 36 (1 to 79) | - |
| Total # of Days | - | 116 | - |
| # of Days per Patient | - | 9.7 | - |
Figure 3.
Safety outcome measures based on a) Renal Function calculated and b) Neutropenia.
Duration of Therapy, Hospitalizations, and Health Care Costs
Treatment-related data and health care costs are outlined in Table 4 and Figure 4. In patients with CMV viremia, GCV-treated patients required a shorter duration of intravenous therapy: 21.5 days (3 to 83 days) compared to 28 days (6 to 88 days) for FOS-treated patients, p=0.35. However, the total duration of therapy (including the duration of oral therapy for patients who were transitioned from intravenous therapy to oral valganciclovir) was longer in the GCV group: 37 days (13 to 164 days) compared to 28 days (6 to 88 days), p=0.21. Of note, this did not shorten the duration of hospitalization, which was similar between both groups: 9 days (0 to 28 days) for GCV and 9 days (0 to 31 days) for FOS, p=0.52. The number of 30-day re-admissions after first discharge and the home health utilization were both higher in the GCV group (two vs zero 30-day readmissions), but the differences were not statistically significant.
Table 4:
Treatment-Related Data
| Ganciclovir (n=52) | Foscarnet (n=12) | P Value | |
|---|---|---|---|
| Days of IV Therapy | 21.5 (3 to 83) | 28 (6 to 88) | 0.35 |
| Total Days of Therapy | 37 (13 to 164) | 28 (6 to 88) | 0.21 |
| Hospitalization Days | 9 (0 to 28) | 9 (0 to 31) | 0.52 |
| 30-Day Readmissions | 2 (4%) | 0 (0%) | 1.00 |
| Total # of Readmit Days | 22 | 0 | - |
| # of Home Health Patients | 12 (23%) | 4 (33%) | 0.48 |
| Median # of Home Health Visits | 32 (7 to 78) | 15.5 (10 to 18) | - |
| Total # of Home Health Visits | 436 | 59 | - |
Figure 4.
Comparison of healthcare costs in patients taking ganciclovir or foscarnet as anti-CMV treatment.
In patients with CMV viremia, hospitalization costs were similar in the GCV and FOS groups ($31,900 vs. $33,800, respectively), while total drug costs were higher in the FOS group: $19,800 vs. $4,600. The estimated sum of the hospitalization and drug costs for the GCV vs. FOS groups was $36,500 vs. $53,600, respectively. After adding costs of hospital re-admission, home health, growth factor, and dialysis the total treatment cost for CMV infection was lower in the GCV group: $38,100 vs. $59,400 for FOS group, p<0.05.
DISCUSSION
The goal of this study was to identify health care costs (treatment burden) associated with GCV versus FOS for the treatment of CMV viremia in patients who underwent alloHCT. This study reaffirmed efficacy and safety data already available in the literature,8,9 and in the prescribing information of the two agents. We evaluated and compared health care costs related to the individual agents, treatment-related hospitalizations or outpatient visits, drug-induced side effects and complications, and supportive care medications.
Before incorporating cost into clinical decision making, it is important to ensure that there are no differences in efficacy between GCV or FOS for CMV PET. Our analysis revealed no statistically significant differences in recurrence of CMV viremia, development of CMV end-organ disease, or mortality among patients treated with GCV or FOS. Furthermore, no statistical difference was detected in the rate of CMV viral clearance (as measured by viral load) with either antiviral agent. Currently, at our center, GCV is recommended as a first-line agent except in cases of neutropenia, GCV resistance, or non-response to GCV (lack of decline of CMV viral load by one log after two weeks of induction therapy) treatment failure. As expected, a trend towards a higher incidence of neutropenia was observed in the GCV group, whereas FOS group experienced more renal impairment requiring dialysis. Interestingly, more patients in the FOS group required filgrastim support, and at a higher dose compared to GCV-treated patients. The most likely explanation for this finding is that as neutropenia is an indication for use of FOS, patients treated with this agent are more likely to be neutropenic, with delayed or poor graft function.
Health care costs associated with use of these two antivirals was evaluated by: duration of therapy, duration of intravenous therapy, hospitalizations, home health, etc. When comparing the drug costs of GCV to FOS, the unit cost of FOS adjusted to a 70 kg individual was four fold higher than GCV. One might anticipate that the availability of an oral prodrug of GCV, valganciclovir (vGCV), would provide the option for GCV patients to change the administration of their antiviral therapy from intravenous to oral, possibly reducing the length of hospitalization. Thus, our initial expectation prior to this study was that FOS-treated patients would likely have longer hospitalization and/or a higher rate of home health utilization. However, in our study, the hospitalization period for treatment of CMV infection was similar between groups. Similar length of hospitalization could be explained by the practical ability to discharge the patients from the hospital to receive home therapy regardless of which agent was used. This should increase the home health care costs for the FOS group since the GCV group would be treated with oral vGCV. Actually, the home health costs were $1,680 in the GCV group and $980 in the FOS group. This could be explained by the fact that some FOS patients were switched to valganciclovir for outpatient use and a longer duration of home health in the ganciclovir group.
GCV appears to have more cost-saving potential for the treatment of CMV infection, and the main driver for the difference between the two agents is the drug cost. Home health, growth factor, and dialysis costs also contributed to the total cost of treatment for both agents, but their impact appears to be minimal relative to drug and hospitalization costs. Another important factor, which should be taken into consideration is the higher re-admission rate in the GCV group. Although we accounted for the additional hospitalization costs, we did not incorporate other costs that may have been incurred with re-admission, e.g., cost of switching from GCV to FOS, and effect on total duration of therapy.
This study carries the inherent limitations of a single center retrospective analysis including a low number of patients, a disproportionate number of patients in GCV and FOS groups, and a high rate of switching between agents. Another limitation of this study is the uncertainty of attributing the length of hospitalization to viremia rather than to multiple comorbidities in this patient population. In addition, because FOS inherently has higher drug costs and is only utilized at our institution in patients where GCV is not an option, it is difficult to identify whether the cost difference between the two groups emanates from the direct/indirect costs of the antiviral agents or the baseline condition of the patients. Furthermore, in this pilot study we analyzed costs directly related to the treatment, without including indirect costs such as risk of infection from GCV-induced neutropenia (secondary bacterial and fungal infections), provider time required to manage therapy, and hospitalizations incurred from complications related to either agent. In a recent study, Robin et al, reported significant transplant costs attributable to CMV infection within the first year after alloHCT. However, they did not discriminate cost by the anti-CMV agent used.15 Similarly, Jain et al, reported an excess cost ranging between $58,000 to $74,000 per patient associated with CMV infection compared to patients who did not have an infection in the first six months after alloHCT.16 Based on the currently available literature, the cost of CMV infection adds significantly to the health resource utilization of alloHCT.15,16 Our study adds to the current literature by documenting a trend towards higher cost and resource utilization with FOS use as compared with GCV (including the toxicity). This information may be particularly helpful for the institutional antimicrobial (antiviral) stewardship programs.
Until recently, there has been a paucity of data surrounding the health care-related costs following pre-emptive treatment of CMV viremia. A recent study by Ueno et al used data from Japanese hospital claims database to compare the aggregate medical costs of patients who experienced CMV reactivation versus patients who did not.11 The main differences between Uneo et al’s study and the current study are that our study itemized specific agent-related costs for GCV and FOS and only included patients with confirmed CMV reactivation who met treatment criteria for pre-emptive antiviral therapy. Ueno et al, report higher medical costs than those observed in our study, which is likely attributable to their cost analysis incorporating more components, including additional medications, blood products, and clinical exams whereas our study focused primarily on the antiviral agent, hospitalization, and adverse event management (e.g. growth factor, dialysis). In a second study, El Haddad et al, evaluated the comparative drug costs of GCV and FOS.10 El Haddad’s evaluated a higher number of patients compared to ours and analyzed the cost per CMV episode, whereas our study evaluated the cost per patient and was restricted to the first reactivation episode. Although they reported a lower mean drug costs, the total cost was higher in their study compared to ours. The higher number of patients and lower drug costs observed in their study may be explained by the fact that our exclusion criteria were more stringent with respect to duration of antiviral utilization. The lower duration of hospitalization seen in our patients may explain the difference in treatment costs or perhaps could be related to the variance in clinical care.
The utilization of GCV and FOS is likely to decline with the approval of letermovir, a novel anti-viral agent that reduced clinically significant CMV infection in a multicenter phase III clinical trial.5 Based on the phase III trial results, the federal drug agency (FDA) approved this agent for prophylaxis to prevent CMV infection in CMV seropositive alloHCT recipients.17 It is anticipated that this major development will decrease the CMV infection in the first 100 days post-alloHCT, although breakthrough and late onset (>100 days post HCT) CMV infection will continue to require PET. It is prudent to make a PET choice based on patient-safety and cost considerations, especially in the context of value-based treatment that is patient centric.
In conclusion, GCV and FOS are equally effective as PET for CMV infection. However, both agents are associated with significant toxicity and health care resource utilization. FOS as compared to GCV, is more likely to be associated with a higher cost of therapy.
ACKNOWLEDGMENTS
The authors thank the City of Hope staff and nurses, as well as the patients and their families, without whom this work would not be possible. This study was partially supported by NIH P30 CA033572 (Biostatistics Core).
Footnotes
CONFLICT OF INTEREST
Justine Ross serves as an advisory board member for Paratek Pharmaceuticals. John Zaia serves as a consultant for bluebird bio, Rampart Bioscience, Inc., and INDuarte Consulting, LLC. Sanjeet Dadwal serves as an investigator, advisory board member, and speaker bureau member for Merck & Co., Inc., investigator for Ansun Biopharma, Inc. and Shire PLC, advisory board member for Jansen Pharmaceutica, Inc. and Clinigen Group plc. The other authors report no potential conflicts of interest.
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