© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Transplant Infectious Disease, ISSN 1398-2273
Valganciclovir versus valacyclovir prophylaxis for prevention of cytomegalovirus: an economic perspective M. Kacer, L. Kielberger, M. Bouda, T. Reischig. Valganciclovir versus valacyclovir prophylaxis for prevention of cytomegalovirus: an economic perspective. Transpl Infect Dis 2015: 17: 334–341. All rights reserved Abstract: Introduction. Valganciclovir (vGCV) and valacyclovir (vACV) are used in cytomegalovirus (CMV) prophylaxis in renal transplant recipients. The aim of this study was to compare the economic impact of both regimens during 1-year follow-up. Methods. A total of 117 renal transplant recipients at risk for CMV were randomized to 3-month prophylaxis either with vGCV (900 mg/day, n = 60) or vACV (8 g/day, n = 57) and their data used in a pharmacoeconomic analysis. The pharmacoeconomic evaluation involved all direct CMV-related expenses in the first year after transplantation. Sensitivity analysis was employed to examine the effects of various prices of antiviral drugs and diagnostic procedures on overall CMV-related costs. Simulation of the more expensive US healthcare perspective was performed, and a scenario involving costs of acute rejection (AR) was examined. Results. Overall CMV-related costs were significantly lower in the vACV arm; median United States dollars (USD) 3473 (3108–3745) vs. USD 5810 (4409–6757; P < 0.001) per patient, respectively. Our data showed that the critical determinant of the major disparity between the prophylactic regimens was the prophylaxis price. Median cost of prophylaxis in the vACV group was USD 1729 (1527– 2173) compared to USD 3968 (2683–4857) in the vGCV group (P < 0.001). In sensitivity analysis of the overall CMV-related costs, the least and the most expensive pharmacotherapy and diagnostic scenarios were used; nevertheless, the vACV arm remained markedly less expensive. Simulation considering the higher physician/nurse and hospitalization fees of the US healthcare system and the scenario including expenditure associated with AR episodes also favored vACV. Conclusion. VACV prophylaxis for CMV is associated with a significant 44% lower cost than vGCV at the first year after renal transplantation.
Cytomegalovirus (CMV) is one of the most common opportunistic pathogens in solid organ transplantation (1). Although direct effects of CMV are becoming less of a concern in the era of rapid diagnostic procedures and potent treatment with ganciclovir (GCV) or valganciclovir (vGCV), its indirect effects remain a major contributor to morbidity in transplant recipients. Both asymptomatic CMV viremia and CMV disease are
334
M. Kacer1,2, L. Kielberger1,2, M. Bouda1,2, T. Reischig1,2 1
Department of Internal Medicine I, Charles University Medical School and Teaching Hospital, Pilsen, Czech Republic, 2Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic
Key words: cytomegalovirus; renal transplantation; valacyclovir; valganciclovir; prevention; economic; cost Correspondence to: Tomas Reischig, MD, PhD, Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Alej Svobody 80, Pilsen 304 60, Czech Republic Tel: +420-37-7103650 Fax: +420-37-7103506 E-mail: [email protected]
Received 16 November 2014, revised 30 January 2015, accepted for publication 28 February 2015 DOI: 10.1111/tid.12383 Transpl Infect Dis 2015: 17: 334–341
capable of altering the (allo)immune response of the host, thus raising the incidence of acute rejection (AR) and chronic allograft injury (2–7). In addition to that, CMV is associated with higher risk of other opportunistic infections, cardiovascular events, or new-onset diabetes mellitus (8, 9). CMV is not only associated with worse graft and patient survival but also with a significant increment in transplant-related expenditure (10–12).
Kacer et al: Valacyclovir vs. valganciclovir for CMV
Prevention of CMV is therefore essential. Preemptive therapy or universal prophylaxis is equally effective in preventing CMV after transplantation. Furthermore, both strategies are considered to be cost-effective (13–18). When CMV indirect effects are included in economic analysis, even expensive prophylactic regimens such as 6-month vGCV definitely seem economical (19). Today, vGCV is the drug used most frequently in prophylaxis. Valacyclovir (vACV), an alternative that can be used for CMV prophylaxis in renal transplant recipients only, might be an attractive choice for economic reasons, with less bone marrow suppression (14, 15). The efficacy and cost-effectiveness of vACV have been demonstrated in randomized trials (20, 21). To date, however, no randomized trial to our knowledge has compared head-to-head vGCV and vACV for CMV prophylaxis in renal transplant recipients from the economic perspective. Using data from a recently published randomized trial (22), we compared the economic impact of vGCV and vACV prophylactic regimens.
Methods Methods will be presented briefly, as they have been thoroughly described previously (22). All patients at risk of CMV with recipient (R) and/or donor (D) positive CMV serology undergoing kidney transplantation in a single center from November 2007 through April 2012 were enrolled in our study. After providing written informed consent, patients were randomized at a 1:1 ratio to 3-month prophylaxis either with vGCV (Valcyte; Hoffman-La Roche, Basel, Switzerland, 900 mg/day [q.d. p.o.]) or with vACV (Valtrex; Glaxo Wellcome, Brentford, UK, 2 g four times a day [q.i.d. p.o.]). Doses were adjusted according to renal function. Whole blood CMV DNAemia was tested at prespecified intervals (biweekly during the first 3 months and at months 4, 5, 6, 9, and 12 thereafter) or when clinically needed. Patients developing CMV disease were treated with vGCV (900 mg twice daily [b.i.d.]). In the case of severe disease, intravenous GCV (Cymevene, HoffmanLa Roche, 5 mg/kg b.i.d.) was administered initially. Asymptomatic CMV DNAemia was not treated.
highly marginal donors (donation after cardiac death, ≥70 years old, donors with hypertension and significant nephrosclerosis on biopsy, and/or dual kidney transplantation) were treated with anti-IL2R monoclonal antibody (Simulect; Novartis Pharmaceuticals, Basel, Switzerland). All patients were given mycophenolate mofetil and corticosteroids, and a prophylaxis course of trimethoprim-sulfamethoxazole for 4 months and oral amphotericin solution for 1 month.
Pharmacoeconomic analysis Economic data were collected prospectively alongside the main clinical trial. The pharmacoeconomic evaluation involved all expenses directly related to CMV in the first year post transplant. These comprised costs of diagnostic procedures used in CMV viremia and disease (polymerase chain reaction [PCR], pp65 antigenemia, serology, blood culture, colonoscopy, biopsy, etc.); costs of drugs used in the prophylaxis and treatment of CMV; and costs associated with outpatient visits (physician/ nurse fees, blood drawing, etc.) or hospitalization. As CMV DNA PCR testing is not clinically necessary while prophylaxis is being administered, expenses arising from per-protocol PCR monitoring during the first 3 months were not included in our analysis. Exact antiviral drug consumption by each and every patient was counted to determine overall drug-related expenditure. Calculations were based upon the reimbursement list developed by the Ministry of Health of the Czech Republic in the year 2013; mean currency exchange rate of 2013 was used to convert monetary data from Czech crowns (CZK) into United States dollars (USD). Input monetary data for antiviral medication were USD 1.59 per vACV 500-mg tablet, USD 29.20 per vGCV 450-mg tablet, and USD 37.10 per GCV 500-mg vial. Regarding diagnostic procedures, the costs per test were as follows: CMV DNA PCR cost USD 275.80, CMV pp65 antigenemia USD 33, CMV serology USD 44.90, and CMV blood culture USD 71.80. Only 1 patient required hospitalization and further diagnostic procedures (colonoscopy, bowel biopsy, etc.), for which we obtained billing directly from his health insurance company. Outpatient visits cost USD 16.70 each.
Immunosuppression Sensitivity analysis Standard-of-care immunosuppressive regimens were based on cyclosporine or tacrolimus. Highly sensitized patients received rabbit anti-thymocyte globulin (Thymoglobulin; Genzyme, Cambridge, Massachusetts, USA) for induction therapy; recipients of grafts from
Sensitivity analysis was employed to simulate the effect of various prices of medication and other expenses on overall costs. First, the least and the most expensive pharmacotherapy scenarios were examined using the
Transplant Infectious Disease 2015: 17: 334–341
335
Kacer et al: Valacyclovir vs. valganciclovir for CMV
Costs of an acute rejection episode in the first year post transplant1
Type of rejection
Standard-criteria donor
Living donor
Extended-criteria donor
Antibody-treated
22,407
19,934
21,986
Steroid-sensitive
14,122
15,633
19,186
1
Based on Gheorghian et al. (24). Costs are expressed in US dollars.
Table 1
lowest and highest prices of antivirals on the market in 2013; these ranged from USD 0.98–4.90 per one 500-mg vACV tablet, USD 12.50–62.60 per one 450-mg vGCV tablet, and USD 6.70–98.40 per one 500-mg GCV vial. Likewise, the least and the most expensive diagnostic scenarios were tested using PCR prices from USD 57.50 to USD 348 (16). Another simulation considered higher costs of physician/nurse fees and hospitalization in the US healthcare system, calculating with costs of USD 4287 per hospitalization and USD 95 per outpatient visit (23). Finally, as fewer episodes of biopsy-proven AR occurred in the vGCV prophylaxis group, a scenario including costs of ARs (Table 1) was used (24).
Statistical analysis All data are presented as median (interquartile range) unless indicated otherwise. Quantitative parametric data were compared using Student’s t-test, and Mann– Whitney U-test was used in non-parametric distribution. Qualitative data were examined using the v2 or Fisher’s exact test. Survival data were calculated using Kaplan– Meier curves. All data were analyzed according to the intention-to-treat principle. Statistical calculations were made using SigmaStat (Systat, San Jose, California, USA) and Statistica 9.0 (StatSoft/Dell, Prague, Czech Republic) software. Values of P < 0.05 were considered statistically significant.
Results Main clinical outcomes A total of 119 kidney transplant recipients were randomized to 3-month prophylaxis either with vACV (n = 59) or vGCV (n = 60) (Fig. 1). The 2 groups did not differ in their demographic and immunological characteristics. The initial immunosuppressive regimen was similar in both groups, except for a higher frequency of basiliximab induction therapy in the vGCV
336
group. All but 8 patients were followed up for 12 months. Of these 8 patients, 7 died or lost their graft, and 1 moved to another country during the first year post transplant. Because of their very short followup (2 and 28 days), 2 of the above patients were excluded from the pharmacoeconomic analysis (Fig. 1). Baseline characteristics of the patients included in the pharmacoeconomic analysis are shown in Table 2. Median dose of antivirals used for prophylaxis was 5.97 (5.18–7.36) g in the vACV group and 657 (458–790) mg in the vGCV group, with no difference in prophylaxis duration (median; 92 [91–93] vs. 92 [91–93] days, respectively, P = 0.405). Cumulative patient and graft survival rates were similar in both groups. Three patients died in the vACV group, and none in the vGCV group (P = 0.073). The 1year graft survival was 95% in both study arms (P = 0.951). CMV disease developed in 1 patient (2%) in the vACV group and in 3 patients (5%) in the vGCV group (P = 0.335). The aforementioned episodes consisted of 3 CMV syndromes and 1 tissue-invasive disease (colitis), all of which responded to treatment with GCV or vGCV. No recurrent or breakthrough CMV disease occurred during prophylaxis. Also, the incidence of CMV DNAemia was similar in both prophylactic regimens (43% vs. 31%, respectively; P = 0.241). A trend was seen toward a higher incidence of biopsy-proven AR in the vACV group (30% vs. 17%, P = 0.074).
Pharmacoeconomic analysis Overall CMV-related costs were significantly lower in the study arm receiving vACV prophylaxis; median USD 3473 (3108–3745) vs. USD 5810 (4409–6757; P < 0.001) per patient. No difference was found in the costs related to CMV infection, diagnostic procedures, or the physician/nurse fees between the groups (Table 3). Also, there was an insignificant dissimilarity in expenses related to CMV disease; however, the small number of events precluded a representative statistical evaluation (Table 4). Our data showed that the critical determinant of the major disparity between the prophylactic regimens was the prophylaxis price (Fig. 2). Median cost of prophylaxis in the vACV group was USD 1729 (1527–2173) compared to USD 3968 (2683– 4857) in the vGCV group (P < 0.001).
Sensitivity analysis In sensitivity analysis of overall CMV-related costs, the least and the most expensive pharmacotherapy scenar-
Transplant Infectious Disease 2015: 17: 334–341
Kacer et al: Valacyclovir vs. valganciclovir for CMV
ios, and the least and the most expensive diagnostic scenarios were used; nevertheless, the vACV arm remained markedly less expensive (Table 5). Also, the difference in prophylaxis-related costs was insensitive to the least (USD 1065 [941–1339] vs. USD 1696 [1147–2076]) and the most expensive (USD 5283 [4668–6640] vs. USD 8516 [5759–10,423]) scenarios (P < 0.001 for both comparisons). Simulation considering higher physician/nurse and hospitalization fees in the US healthcare system did not change the pattern of the results, with the median overall CMV-related costs being then USD 3904 (3540–4183) in the vACV group vs. USD 6254 (4800–7150) in the vGCV group (P < 0.001). A scenario including expenditure associated with ARs also favored vACV (USD 3745 [3400– 18,565] vs. USD 6180 [4792–7223]; P < 0.001).
Characteristics of the study population Valganciclovir (n = 60)
Valacyclovir (n = 57)
P-value
48 13
50 11
0.238
47 (78)
37 (65)
0.159
Chronic glomerulonephritis
30 (50)
21 (36)
0.212
Polycystic kidney disease
14 (23)
10 (18)
0.585
6 (10)
10 (19)
0.359
Variables Recipient Age (years; mean SD) Gender (male) Cause of renal disease
Hypertensive nephrosclerosis Diabetic nephropathy
2 (3)
6 (10)
0.240
Chronic interstitial nephritis
2 (3)
4 (7)
0.629
Other
6 (10)
6 (10)
0.833
Previous transplantation
9 (15)
7 (12)
0.874
Pretransplant PRA ≥20%
11 (18)
8 (14)
0.704
Discussion
CMV serostatus 4 (7)
0.470
D+/R+
D+/R
44 (73)
7 (12)
47 (82)
0.335
D /R+
9 (15)
6 (10)
0.655
50 16
49 16
0.678
57 (95)
52 (91)
0.659
Donor Age (years; mean SD) Donor type (deceased) Expanded-criteria donor
1
34 (57)
30 (53)
0.801
Donation after cardiac death
3 (5)
3 (6)
0.723
Dual kidney transplantation
5 (9)
3 (6)
0.771
Cyclosporine + mycophenolate mofetil
25 (42)
35 (61)
0.051
Tacrolimus + mycophenolate mofetil
35 (58)
22 (39)
0.051
No induction therapy
25 (42)
34 (60)
0.079
Basiliximab
26 (43)
13 (23)
0.031
9 (15)
10 (18)
0.903
Anti-thymocyte globulin 1
According to the United Network for Organ Sharing criteria. Data are no. (%) unless indicated otherwise. SD, standard deviation; PRA, panel reactive antibodies; CMV, cytomegalovirus; D, donor; R, recipient.
Table 2
In this study, we analyzed economic data obtained in a prospective randomized study comparing 3-month CMV prophylaxis with vACV or vGCV after renal transplantation (22). After calculation of all costs directly related to CMV management, vACV prophylaxis was significantly less expensive, saving approximately USD 2500 per 1 treated patient using prices in 2013. Given the comparable efficacy of both drugs in the prevention of CMV disease and viremia, the difference was a result of the higher price of vGCV vs. vACV used in prophylaxis. With regard to other parameters, such as the costs related to CMV disease, DNAemia management, PCR CMV monitoring, other diagnostic procedures, or the physician/nurse fees, both regimens were comparable. While the cost-effectiveness of CMV prevention is generally recognized, the economically most advantageous strategy is yet to be defined. The direct CMV disease-related costs vary between USD 15,000 and USD 26,000, rising appreciably when including indirect CMV effects (16, 19, 21, 24, 25). At present, vGCV is the most frequently used antiviral agent in CMV prophylaxis (14, 26). Economic models have suggested vGCV is cost-effective in 3-month prophylaxis in intermediaterisk patients and in 6-month prophylaxis in high-risk patients (19, 25). The problem is that vGCV prophylaxis is relatively costly (17). Likewise, vACV prophylaxis has been shown to be cost-effective compared with placebo. However, these analyses are based on data obtained from earlier trials using immunosuppressive
Transplant Infectious Disease 2015: 17: 334–341
337
Kacer et al: Valacyclovir vs. valganciclovir for CMV
Fig. 1. Flow of patients through the study. CMV, cytomegalovirus; D, donor; R, recipient. Analysis of overall cytomegalovirus (CMV)-related costs
Variables
Valganciclovir (n = 60)
Characteristics of cytomegalovirus (CMV) DNAemia and disease episodes
Valacyclovir (n = 57)
P-value
Valganciclovir versus valacyclovir prophylaxis for prevention of cytomegalovirus: an economic perspective M. Kacer, L. Kielberger, M. Bouda, T. Reischig. Valganciclovir versus valacyclovir prophylaxis for prevention of cytomegalovirus: an economic perspective. Transpl Infect Dis 2015: 17: 334–341. All rights reserved Abstract: Introduction. Valganciclovir (vGCV) and valacyclovir (vACV) are used in cytomegalovirus (CMV) prophylaxis in renal transplant recipients. The aim of this study was to compare the economic impact of both regimens during 1-year follow-up. Methods. A total of 117 renal transplant recipients at risk for CMV were randomized to 3-month prophylaxis either with vGCV (900 mg/day, n = 60) or vACV (8 g/day, n = 57) and their data used in a pharmacoeconomic analysis. The pharmacoeconomic evaluation involved all direct CMV-related expenses in the first year after transplantation. Sensitivity analysis was employed to examine the effects of various prices of antiviral drugs and diagnostic procedures on overall CMV-related costs. Simulation of the more expensive US healthcare perspective was performed, and a scenario involving costs of acute rejection (AR) was examined. Results. Overall CMV-related costs were significantly lower in the vACV arm; median United States dollars (USD) 3473 (3108–3745) vs. USD 5810 (4409–6757; P < 0.001) per patient, respectively. Our data showed that the critical determinant of the major disparity between the prophylactic regimens was the prophylaxis price. Median cost of prophylaxis in the vACV group was USD 1729 (1527– 2173) compared to USD 3968 (2683–4857) in the vGCV group (P < 0.001). In sensitivity analysis of the overall CMV-related costs, the least and the most expensive pharmacotherapy and diagnostic scenarios were used; nevertheless, the vACV arm remained markedly less expensive. Simulation considering the higher physician/nurse and hospitalization fees of the US healthcare system and the scenario including expenditure associated with AR episodes also favored vACV. Conclusion. VACV prophylaxis for CMV is associated with a significant 44% lower cost than vGCV at the first year after renal transplantation.
Cytomegalovirus (CMV) is one of the most common opportunistic pathogens in solid organ transplantation (1). Although direct effects of CMV are becoming less of a concern in the era of rapid diagnostic procedures and potent treatment with ganciclovir (GCV) or valganciclovir (vGCV), its indirect effects remain a major contributor to morbidity in transplant recipients. Both asymptomatic CMV viremia and CMV disease are
334
M. Kacer1,2, L. Kielberger1,2, M. Bouda1,2, T. Reischig1,2 1
Department of Internal Medicine I, Charles University Medical School and Teaching Hospital, Pilsen, Czech Republic, 2Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic
Key words: cytomegalovirus; renal transplantation; valacyclovir; valganciclovir; prevention; economic; cost Correspondence to: Tomas Reischig, MD, PhD, Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Alej Svobody 80, Pilsen 304 60, Czech Republic Tel: +420-37-7103650 Fax: +420-37-7103506 E-mail: [email protected]
Received 16 November 2014, revised 30 January 2015, accepted for publication 28 February 2015 DOI: 10.1111/tid.12383 Transpl Infect Dis 2015: 17: 334–341
capable of altering the (allo)immune response of the host, thus raising the incidence of acute rejection (AR) and chronic allograft injury (2–7). In addition to that, CMV is associated with higher risk of other opportunistic infections, cardiovascular events, or new-onset diabetes mellitus (8, 9). CMV is not only associated with worse graft and patient survival but also with a significant increment in transplant-related expenditure (10–12).
Kacer et al: Valacyclovir vs. valganciclovir for CMV
Prevention of CMV is therefore essential. Preemptive therapy or universal prophylaxis is equally effective in preventing CMV after transplantation. Furthermore, both strategies are considered to be cost-effective (13–18). When CMV indirect effects are included in economic analysis, even expensive prophylactic regimens such as 6-month vGCV definitely seem economical (19). Today, vGCV is the drug used most frequently in prophylaxis. Valacyclovir (vACV), an alternative that can be used for CMV prophylaxis in renal transplant recipients only, might be an attractive choice for economic reasons, with less bone marrow suppression (14, 15). The efficacy and cost-effectiveness of vACV have been demonstrated in randomized trials (20, 21). To date, however, no randomized trial to our knowledge has compared head-to-head vGCV and vACV for CMV prophylaxis in renal transplant recipients from the economic perspective. Using data from a recently published randomized trial (22), we compared the economic impact of vGCV and vACV prophylactic regimens.
Methods Methods will be presented briefly, as they have been thoroughly described previously (22). All patients at risk of CMV with recipient (R) and/or donor (D) positive CMV serology undergoing kidney transplantation in a single center from November 2007 through April 2012 were enrolled in our study. After providing written informed consent, patients were randomized at a 1:1 ratio to 3-month prophylaxis either with vGCV (Valcyte; Hoffman-La Roche, Basel, Switzerland, 900 mg/day [q.d. p.o.]) or with vACV (Valtrex; Glaxo Wellcome, Brentford, UK, 2 g four times a day [q.i.d. p.o.]). Doses were adjusted according to renal function. Whole blood CMV DNAemia was tested at prespecified intervals (biweekly during the first 3 months and at months 4, 5, 6, 9, and 12 thereafter) or when clinically needed. Patients developing CMV disease were treated with vGCV (900 mg twice daily [b.i.d.]). In the case of severe disease, intravenous GCV (Cymevene, HoffmanLa Roche, 5 mg/kg b.i.d.) was administered initially. Asymptomatic CMV DNAemia was not treated.
highly marginal donors (donation after cardiac death, ≥70 years old, donors with hypertension and significant nephrosclerosis on biopsy, and/or dual kidney transplantation) were treated with anti-IL2R monoclonal antibody (Simulect; Novartis Pharmaceuticals, Basel, Switzerland). All patients were given mycophenolate mofetil and corticosteroids, and a prophylaxis course of trimethoprim-sulfamethoxazole for 4 months and oral amphotericin solution for 1 month.
Pharmacoeconomic analysis Economic data were collected prospectively alongside the main clinical trial. The pharmacoeconomic evaluation involved all expenses directly related to CMV in the first year post transplant. These comprised costs of diagnostic procedures used in CMV viremia and disease (polymerase chain reaction [PCR], pp65 antigenemia, serology, blood culture, colonoscopy, biopsy, etc.); costs of drugs used in the prophylaxis and treatment of CMV; and costs associated with outpatient visits (physician/ nurse fees, blood drawing, etc.) or hospitalization. As CMV DNA PCR testing is not clinically necessary while prophylaxis is being administered, expenses arising from per-protocol PCR monitoring during the first 3 months were not included in our analysis. Exact antiviral drug consumption by each and every patient was counted to determine overall drug-related expenditure. Calculations were based upon the reimbursement list developed by the Ministry of Health of the Czech Republic in the year 2013; mean currency exchange rate of 2013 was used to convert monetary data from Czech crowns (CZK) into United States dollars (USD). Input monetary data for antiviral medication were USD 1.59 per vACV 500-mg tablet, USD 29.20 per vGCV 450-mg tablet, and USD 37.10 per GCV 500-mg vial. Regarding diagnostic procedures, the costs per test were as follows: CMV DNA PCR cost USD 275.80, CMV pp65 antigenemia USD 33, CMV serology USD 44.90, and CMV blood culture USD 71.80. Only 1 patient required hospitalization and further diagnostic procedures (colonoscopy, bowel biopsy, etc.), for which we obtained billing directly from his health insurance company. Outpatient visits cost USD 16.70 each.
Immunosuppression Sensitivity analysis Standard-of-care immunosuppressive regimens were based on cyclosporine or tacrolimus. Highly sensitized patients received rabbit anti-thymocyte globulin (Thymoglobulin; Genzyme, Cambridge, Massachusetts, USA) for induction therapy; recipients of grafts from
Sensitivity analysis was employed to simulate the effect of various prices of medication and other expenses on overall costs. First, the least and the most expensive pharmacotherapy scenarios were examined using the
Transplant Infectious Disease 2015: 17: 334–341
335
Kacer et al: Valacyclovir vs. valganciclovir for CMV
Costs of an acute rejection episode in the first year post transplant1
Type of rejection
Standard-criteria donor
Living donor
Extended-criteria donor
Antibody-treated
22,407
19,934
21,986
Steroid-sensitive
14,122
15,633
19,186
1
Based on Gheorghian et al. (24). Costs are expressed in US dollars.
Table 1
lowest and highest prices of antivirals on the market in 2013; these ranged from USD 0.98–4.90 per one 500-mg vACV tablet, USD 12.50–62.60 per one 450-mg vGCV tablet, and USD 6.70–98.40 per one 500-mg GCV vial. Likewise, the least and the most expensive diagnostic scenarios were tested using PCR prices from USD 57.50 to USD 348 (16). Another simulation considered higher costs of physician/nurse fees and hospitalization in the US healthcare system, calculating with costs of USD 4287 per hospitalization and USD 95 per outpatient visit (23). Finally, as fewer episodes of biopsy-proven AR occurred in the vGCV prophylaxis group, a scenario including costs of ARs (Table 1) was used (24).
Statistical analysis All data are presented as median (interquartile range) unless indicated otherwise. Quantitative parametric data were compared using Student’s t-test, and Mann– Whitney U-test was used in non-parametric distribution. Qualitative data were examined using the v2 or Fisher’s exact test. Survival data were calculated using Kaplan– Meier curves. All data were analyzed according to the intention-to-treat principle. Statistical calculations were made using SigmaStat (Systat, San Jose, California, USA) and Statistica 9.0 (StatSoft/Dell, Prague, Czech Republic) software. Values of P < 0.05 were considered statistically significant.
Results Main clinical outcomes A total of 119 kidney transplant recipients were randomized to 3-month prophylaxis either with vACV (n = 59) or vGCV (n = 60) (Fig. 1). The 2 groups did not differ in their demographic and immunological characteristics. The initial immunosuppressive regimen was similar in both groups, except for a higher frequency of basiliximab induction therapy in the vGCV
336
group. All but 8 patients were followed up for 12 months. Of these 8 patients, 7 died or lost their graft, and 1 moved to another country during the first year post transplant. Because of their very short followup (2 and 28 days), 2 of the above patients were excluded from the pharmacoeconomic analysis (Fig. 1). Baseline characteristics of the patients included in the pharmacoeconomic analysis are shown in Table 2. Median dose of antivirals used for prophylaxis was 5.97 (5.18–7.36) g in the vACV group and 657 (458–790) mg in the vGCV group, with no difference in prophylaxis duration (median; 92 [91–93] vs. 92 [91–93] days, respectively, P = 0.405). Cumulative patient and graft survival rates were similar in both groups. Three patients died in the vACV group, and none in the vGCV group (P = 0.073). The 1year graft survival was 95% in both study arms (P = 0.951). CMV disease developed in 1 patient (2%) in the vACV group and in 3 patients (5%) in the vGCV group (P = 0.335). The aforementioned episodes consisted of 3 CMV syndromes and 1 tissue-invasive disease (colitis), all of which responded to treatment with GCV or vGCV. No recurrent or breakthrough CMV disease occurred during prophylaxis. Also, the incidence of CMV DNAemia was similar in both prophylactic regimens (43% vs. 31%, respectively; P = 0.241). A trend was seen toward a higher incidence of biopsy-proven AR in the vACV group (30% vs. 17%, P = 0.074).
Pharmacoeconomic analysis Overall CMV-related costs were significantly lower in the study arm receiving vACV prophylaxis; median USD 3473 (3108–3745) vs. USD 5810 (4409–6757; P < 0.001) per patient. No difference was found in the costs related to CMV infection, diagnostic procedures, or the physician/nurse fees between the groups (Table 3). Also, there was an insignificant dissimilarity in expenses related to CMV disease; however, the small number of events precluded a representative statistical evaluation (Table 4). Our data showed that the critical determinant of the major disparity between the prophylactic regimens was the prophylaxis price (Fig. 2). Median cost of prophylaxis in the vACV group was USD 1729 (1527–2173) compared to USD 3968 (2683– 4857) in the vGCV group (P < 0.001).
Sensitivity analysis In sensitivity analysis of overall CMV-related costs, the least and the most expensive pharmacotherapy scenar-
Transplant Infectious Disease 2015: 17: 334–341
Kacer et al: Valacyclovir vs. valganciclovir for CMV
ios, and the least and the most expensive diagnostic scenarios were used; nevertheless, the vACV arm remained markedly less expensive (Table 5). Also, the difference in prophylaxis-related costs was insensitive to the least (USD 1065 [941–1339] vs. USD 1696 [1147–2076]) and the most expensive (USD 5283 [4668–6640] vs. USD 8516 [5759–10,423]) scenarios (P < 0.001 for both comparisons). Simulation considering higher physician/nurse and hospitalization fees in the US healthcare system did not change the pattern of the results, with the median overall CMV-related costs being then USD 3904 (3540–4183) in the vACV group vs. USD 6254 (4800–7150) in the vGCV group (P < 0.001). A scenario including expenditure associated with ARs also favored vACV (USD 3745 [3400– 18,565] vs. USD 6180 [4792–7223]; P < 0.001).
Characteristics of the study population Valganciclovir (n = 60)
Valacyclovir (n = 57)
P-value
48 13
50 11
0.238
47 (78)
37 (65)
0.159
Chronic glomerulonephritis
30 (50)
21 (36)
0.212
Polycystic kidney disease
14 (23)
10 (18)
0.585
6 (10)
10 (19)
0.359
Variables Recipient Age (years; mean SD) Gender (male) Cause of renal disease
Hypertensive nephrosclerosis Diabetic nephropathy
2 (3)
6 (10)
0.240
Chronic interstitial nephritis
2 (3)
4 (7)
0.629
Other
6 (10)
6 (10)
0.833
Previous transplantation
9 (15)
7 (12)
0.874
Pretransplant PRA ≥20%
11 (18)
8 (14)
0.704
Discussion
CMV serostatus 4 (7)
0.470
D+/R+
D+/R
44 (73)
7 (12)
47 (82)
0.335
D /R+
9 (15)
6 (10)
0.655
50 16
49 16
0.678
57 (95)
52 (91)
0.659
Donor Age (years; mean SD) Donor type (deceased) Expanded-criteria donor
1
34 (57)
30 (53)
0.801
Donation after cardiac death
3 (5)
3 (6)
0.723
Dual kidney transplantation
5 (9)
3 (6)
0.771
Cyclosporine + mycophenolate mofetil
25 (42)
35 (61)
0.051
Tacrolimus + mycophenolate mofetil
35 (58)
22 (39)
0.051
No induction therapy
25 (42)
34 (60)
0.079
Basiliximab
26 (43)
13 (23)
0.031
9 (15)
10 (18)
0.903
Anti-thymocyte globulin 1
According to the United Network for Organ Sharing criteria. Data are no. (%) unless indicated otherwise. SD, standard deviation; PRA, panel reactive antibodies; CMV, cytomegalovirus; D, donor; R, recipient.
Table 2
In this study, we analyzed economic data obtained in a prospective randomized study comparing 3-month CMV prophylaxis with vACV or vGCV after renal transplantation (22). After calculation of all costs directly related to CMV management, vACV prophylaxis was significantly less expensive, saving approximately USD 2500 per 1 treated patient using prices in 2013. Given the comparable efficacy of both drugs in the prevention of CMV disease and viremia, the difference was a result of the higher price of vGCV vs. vACV used in prophylaxis. With regard to other parameters, such as the costs related to CMV disease, DNAemia management, PCR CMV monitoring, other diagnostic procedures, or the physician/nurse fees, both regimens were comparable. While the cost-effectiveness of CMV prevention is generally recognized, the economically most advantageous strategy is yet to be defined. The direct CMV disease-related costs vary between USD 15,000 and USD 26,000, rising appreciably when including indirect CMV effects (16, 19, 21, 24, 25). At present, vGCV is the most frequently used antiviral agent in CMV prophylaxis (14, 26). Economic models have suggested vGCV is cost-effective in 3-month prophylaxis in intermediaterisk patients and in 6-month prophylaxis in high-risk patients (19, 25). The problem is that vGCV prophylaxis is relatively costly (17). Likewise, vACV prophylaxis has been shown to be cost-effective compared with placebo. However, these analyses are based on data obtained from earlier trials using immunosuppressive
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Kacer et al: Valacyclovir vs. valganciclovir for CMV
Fig. 1. Flow of patients through the study. CMV, cytomegalovirus; D, donor; R, recipient. Analysis of overall cytomegalovirus (CMV)-related costs
Variables
Valganciclovir (n = 60)
Characteristics of cytomegalovirus (CMV) DNAemia and disease episodes
Valacyclovir (n = 57)
P-value
