Cost-effectiveness analysis and budgetary impact of anidulafungin treatment for patients with candidemia and other forms of invasive candidiasis in Brazil

ABSTRACT

Candidemia and other forms of invasive candidiasis (C/IC) are serious conditions, especially for immunosuppressed individuals with prolonged hospitalization in intensive care units (ICU). This study analyzed the incremental cost-effectiveness and budgetary impact (BI) of treatment for IC with anidulafungin compared to amphotericin B lipid complex (ABLC) and amphotericin B deoxycholate (ABD) or conventional amphotericin B (CAB), in the Brazilian Unified Health System (SUS). A decision model was conducted with a time horizon of two weeks from the perspective of SUS. The primary effectiveness endpoints were survival and treatment response rate. All patients were followed up until successful therapy or death. BI analysis was performed based on the measured demand method. A five-year time horizon was adopted based on the number of hospitalizations (per 1,000 hospitalizations). For effectiveness measured in the successful response rate (SRR), anidulafungin dominated the ABLC and ABD formulations. In the results of the analysis with the effectiveness measured according to survival, anidulafungin had a better cost-effectiveness ratio (R$988.26/survival) compared to ABD (R$16,359.50/survival). The BI estimate related to the incorporation of anidulafungin suggests savings of approximately 148 million reais in 5 years when comparing it to ABD. The economic evaluation of anidulafungin and its comparators found it to be cost-effective. The consensus of international scientific societies recommends it as a first-line drug for IC, and its incorporation by SUS would be important.

Cost-benefit analysis; Anidulafungin; Candidemia; Echinocandins; Invasive candidiasis

INTRODUCTION

Invasive candidiasis (IC) and candidemia are infections caused by the Candida species – serious and often identified in immunocompromised patients and those with serious underlying diseases, treated in intensive care units (ICUs)¹,², and with a mortality rate of approximately 40%³. In Brazil, according to the Ministry of Health (MS), there are no national data on its occurrence and extent⁴. However, Colombo et al.⁵ analyzed data from 11 medical centers located in 9 Brazilian capital cities that identified an incidence rate of 2.49 cases of candidemia per 1,000 hospital admissions and 0.37 cases per 1,000 patients/day, a rate 2 to 15 times higher than those reported in other European countries or in the United States⁴-⁶.

The international guidelines recommend echinocandins (caspofungin, micafungin, and anidulafungin) for the treatment of these systemic mycoses given their activity, rarity of resistance, safety profile, and better clinical results when compared to fluconazole and other medicines. As a second-line or rescue therapy, amphotericin B deoxycholate (ABD) and amphotericin B lipid complex (ABLC)³ were used. The National Health Surveillance Agency (ANVISA) suggests anidulafungin as the first-choice treatment for candidemia, providing a loading dose of 200 mg, followed by 100 mg/day. In case of refractoriness, unavailability, or resistance, the following are recommended: one of the lipid formulations of amphotericin B, liposomal amphotericin B (LAB), at a dose of 3 mg/kg/day; or intravenous (IV) ABLC at a dose of 5 mg/kg/day. Treatment should be continued for 2 weeks after negative blood cultures and clinical improvement (usually after 5 to 7 days)¹. In Brazil, itraconazole and ABLC are incorporated into the strategic stock of MS for the treatment of C/IC within the Brazilian Unified Health System (SUS)⁷. The direct costs associated with these diseases include the length of hospital stay, antifungal pharmacotherapy, and those related to the treatment of adverse events (AEs), which can reach US$300 million/year⁸-¹⁰.

This study analyzed the incremental cost-effectiveness and budgetary impact of treatment for C/IC with anidulafungin compared to ABLC and ABD in SUS.

MATERIALS AND METHODS

The population consisted of patients 16 years of age or older with candidiasis or other forms of C/IC determined by culture⁹,¹¹,¹². The perspective adopted was that of SUS. The time horizon of the cost-effectiveness analysis was 14 days⁸,⁹,¹¹ and no discount rate was applied (horizon of less than one year).

The following were used as comparators: (a) ABD or conventional amphotericin B (CAB); and (b) ABLC. The type of alternative therapy depends on the cause of discontinuation of the initial therapy⁹,¹¹. The model outcomes were treatment success as measured by survival (SARR) and treatment response rate (SRR). The patients were followed up until therapeutic success or death¹³,¹⁴. The estimates referring to direct medical costs comprised the identification, measurement, and valuation of the resources used. The uncertainties were evaluated in the sensitivity analysis.

The treatment of C/IC was adopted as described in the Anidulafungin Recommendation Report for the treatment of patients with IC¹⁴: (a) anidulafungin (200 mg/IV on day 1 [D1] and 100 mg daily/IV thereafter) for one week, followed by fluconazole (400 mg – 600 mg/kg daily) IV or orally¹³; (b) ABLC at a dose of 5 mg/kg/day, once a day, for 2 weeks; and (c) ABD at a dose of 0.5 to 1.0 mg/kg IV once a day, with slow infusion for over 4 to 6 h, for 2 weeks. ABLC was used as rescue therapy for anidulafungin¹ and ABD and fluconazole for ABLC¹⁵.

To estimate the total cost of each treatment, the daily maintenance dosages were considered. The prices were extracted from the Health Price Database (BPS)¹⁶, and the records are from 12/21/2021 to 06/21/2022. A weighted average of the amounts paid for the quantities purchased was used. Values for the procedures, exams, and tests were obtained from SUS Procedures, Medicines, and OPM Table Management System (SIGTAP)¹⁷. The resources used were valued in reais. In-hospital treatment considered the use of the indicated medication, along with monitoring the toxic and adverse effects associated with the use of ABD and ABLC. The amount paid by SUS for 4 days of treatment is R$ 465.31. International studies⁸,⁹,¹² had important contributions to the number of queries. All the ICU patients underwent renal function tests, liver function tests, blood counts, and electrolyte tests 2–3 times a week. Table 1 shows that the costs imputed in the model are derived from the diagnosis of fungal infection, the duration of hospital treatment, hospitalization costs, the management of AEs, and drug costs, in addition to the parameters used.

Table 1
Parameters and costs of the economic model

Procedures/Drugs/Treatments (Base case)	Costs (R$) (Amounts for 2022)
Drugs for pharmacotherapy	Unit cost	Daily cost	Source
Primary treatment — Loading dose
ABD 50 mg (1 mg/kg/day)	25.21	35.29	Brasil. Ministério da Saúde16
Anidulafungin 100 mg lyophilized powder (200 mg/day)	259.49	518.98	Brasil. Ministério da Saúde16
ABLC 5 mg/mL Flagon 20 mL	569.35	1,992.72	***
Fluconazole 2 mg/mL (bag 100 mL) (800 mg/day)	13.02	52.08	Brasil. Ministério da Saúde16
Fluconazole 100 mg capsule	13.79	-
Maintenance dose
ABD ampoule Flagon 50 mg	25.21	35.29	Brasil. Ministério da Saúde16
Anidulafungin 100 mg/day lyophilized powder (100 mg/day)	259.49	259.49	Brasil. Ministério da Saúde16
ABLC 5 mg/mL Flagon 20 mL	569.35	1,992.72	***
Fluconazole 2 mg/mL (bag 100 mL) (400 mg/day)	13.02	26.04	Brasil. Ministério da Saúde16
Fluconazole 100 mg capsule (400 mg/day)	13.79	55.16	Brasil. Ministério da Saúde16
Hospitalization and care	Unit	Unit cost	Source
Adult intensive care unit daily II (ICU II)*	1	478.72	Brasil. Ministério da Saúde16
Daily hospitalization for mycoses**	1	224.66	Brasil. Ministério da Saúde16
Outpatient consultation/medical consultation specialized care	1	10.00	Brasil. Ministério da Saúde16
Mycoses treatment	1	116.33	Brasil. Ministério da Saúde16
Other hospital costs	(% of utilization)	Unit cost	Source
		194.12	Brasil. Ministério da Saúde16
Treatment of acute renal failure		246.89
Installation of a double lumen catheter	80 (in ICU)	112.48	Brasil. Ministério da Saúde16
Model parameters
Variable	Measure		Source
Absolute effectiveness of treatment (%)****
Anidulafungin	77.49		Mills et al.13
Fluconazole	63		Mills et al.13
ABD	65.4		Mills et al.13
ABLC*****	72.98		Mills et al.13
Absolute effectiveness of treatment measured by mortality (%)
Anidulafungin	20.75		Mills et al.13
Fluconazole	28.44		Mills et al.13
ABD	30.93		Mills et al.13
ABLC**	39.99		Mills et al.13
Mortality from all causes (RR)
Fluconazole versus ABD	0.88 (CI 95%: 0.74 –1.05)		Mills et al.13
Anidulafungin versus ABD	1.01 (CI 95%: 0.84 –1.20)		Mills et al.13
Anidulafungin versus ABLC	1.01 (CI 95%: 0.84 –1.20)		Mills et al.13
Anidulafungin versus fluconazole	0.73 (CI 95%: 0.48 –1.10)		Mills et al.13
IV treatment duration for successful treatment patients and their survival (days)	14		Mills et al.13
Model parameters
Variable	Measure		Source
Relevant AE
Nephrotoxicity probability for ABD (%)	33.7		Ou et al.8
Fluconazole nephrotoxicity RR compared to that of amphotericin	0.22 (CI 95%: 0.15 –0.32)		Wang et al.14
Anidulafungin nephrotoxicity RR compared to that of amphotericin	0.31 (CI 95%: 0.17 –0.57)		Wang et al.14
Average therapy time
Duration of additional hospitalization time (days)	7 (CI 95%: 5.7 – 8.4)		Ou et al.8
Time needed to determine clinical failure (days)	5		Ou et al.8
Follow-up time (in weeks)	6		Ou et al.8
Length of hospital stay in ICU (days) a
Success and then survival	7		Ou et al.8
Success and then death	7		Ou et al.8
Failure and then survival	14		Ou et al.8
Failure and then death	14		Ou et al.8
Success and then survival	23		Ou et al.8
Success and then death	23		Ou et al.8
Failure and then survival	23		Ou et al.8
Failure and then death	23		Ou et al.8

• IV = intravenous; *R$410.92 referring to hospital services and R$67.80 to professional services; **The daily rates were calculated based on information from June 2022, using the average amount for hospitalization due to mycoses and dividing it by the average hospitalization time (R$2,246.61 in 10 days); ***ABLC 5 mg/mL – 20 mL prices, unit amount of R$569.35, and LAB 50 mg/mL – 20 mL, US$16.25 in December 7, 2021, were provided by the technical area of the SVS/MS; ICU = intensive care unit; CI = confidence interval; RR = relative risk; ****Absolute treatment efficacy and likelihood of each treatment being the best in mixed treatment comparisons using response data from confirmed infection studies; *****Approximation of LAB.

The estimates of efficacy and rates of therapeutic change and other model parameters were obtained from sources listed in Table 1 and not from primary studies. All the expenses were covered by SUS. The patients remained hospitalized throughout the study period and the antifungal therapy failed only once (if the patients switched therapy after the failure of the initial therapy, the alternative therapy was considered successful)⁹. The effectiveness of ABLC was assumed to be similar to that of LAB¹⁵,¹⁸,¹⁹.

An analytical decision model (Figure 1) was developed for the economic evaluation of the primary treatment of C/IC in patients 16 years of age or older who had candidiasis or other forms of HF using (a) anidulafungin, (b) ABLC, and (c) ABD. For the development of the model, Microsoft Excel was used. The models of Auzinger et al.¹², Grau et al.¹⁰, Neoh et al.⁹ and Ou et al.⁸ served as the basis for the development of this work.

Figure 1
Decision tree for the pharmacotherapeutic treatment of C/IC. Adapted from Auzinger et al.12. C/IC = Candidemia; IC = invasive candidiasis; ABLC = amphotericin B lipid complex; ABD = amphotericin B deoxycholate; (+) = treatment path.

A successful IV treatment may last for 14 days. In case of failure, the therapy is changed according to the initial therapy scheme. For anidulafungin and ABD, ABLC is used in the rescue, while for ABLC, fluconazole is used in the rescue. For patients who experience clinical failure and are switched to another type of treatment, the infection is assumed to be suppressed. These subjects received an additional 14 days of second-line treatment and were followed up for 6 weeks or until death.

Budget impact analysis (BIA) was performed by comparing the use of anidulafungin with ABD in patients with C/IC to assess its incorporation into SUS. The method of measured demand was used. The costs and probabilities of candidiasis, death, and survival were those of the economic assessment. According to estimates by MS,⁴ the incidence of candidiasis is 18 and 135 new cases per 100,000 inhabitants, and the lowest rate was used. The perspective adopted was from SUS and the time horizon was not stipulated as its calculation is associated with the number of hospitalizations (per 1,000 hospitalizations). Ethical approval was not required.

RESULTS

The incremental cost-effectiveness ratio (ICER) was calculated as the ratio between the difference in direct medical costs and drug acquisition costs, and effectiveness, as the difference in the absolute response rate measured by treatment success and survival. In both alternatives, as shown in Table 2, the use of ABLC is a domination strategy, while anidulafungin has a better cost-effectiveness ratio (R$832.14/SRR). For the effectiveness measured in survival, anidulafungin has a better cost-effectiveness ratio (R$ 988.26/SARR) compared to ABD (R$ 16,359.50/SARR).

Table 2
Incremental cost-effectiveness ratio of treatment strategies

according to absolute response rate as measured by treatment success (SRR)
Strategy	Costs (R$)	∆ Costs (R$)	Effectiveness (SRR)	∆ Effectiveness (SRR)	ICER (R$/SRR)
ABD	11,299.51	-	0.654	-
Anidulafungin	11,400.11	100.61	0.7749	0.12	832.14
ABLC	16,379.29	4,979.17	0.7298	0.05	Dominated
according to survival absolute response rate (SARR)
Strategy	Costs (R$)	∆ Costs	Effectiveness (SARR)	∆ Effectiveness (SARR)	ICER (R$/SARR)
ABD	11,299.51	-	0.6907	-
Anidulafungin	11,400.11	100.61	0.7925	0.10	988.26
ABLC	16,379.29	4,979.17	0.6001	0.19	Dominated

• ICER = incremental cost-effectiveness ratio.

Deterministic univariate sensitivity analysis was performed, varying the absolute response rate by 10% and the probability of needing dialysis in patients with nephrotoxicity (50% for ABD)². In this scenario, ABD was dominated by anidulafungin. Other scenarios did not change the cost-effectiveness ratio of anidulafungin, as shown in Table 3.

Table 3
Univariate deterministic analysis.

Medication	Basal variable	Results	ICER (∆ Costs/∆ Effectiveness)
Absolute therapeutic success response rate
Anidulafungin	0.69741	12,185.39	7,327.39
	0.7749	11,400.11	832.14
	0.85239	10,614.84	ABD dominated
ABD	0.5886	12,179.46	18,623.03
	0.654	11,299.51	17,277.54
	0.7194	10,419.55	15,932.04
Dialysis probability
Anidulafungin	0.27234	11,229.90	ABD dominated
	0.3026	11,400.11	832.14
	0.33286	11,632.18	2,751.58
ABD	0.27234	10,750.43	16,437.97
	0.3026	11,299.51	17,277.54
	0.33286	12,048.09	ABD dominated
Probability of patients with an AE to develop nephrotoxicity
ABD	50%	11,892.68	ABD dominated
Survival absolute response rate
Anidulafungin	0.813		820.93
	0.793		988.26
	0.772		1,241.27
ABD	0.722		15,658.31
	0.691		16,359.50
	0.660		17,126.44

• ICER = incremental cost-effectiveness ratio; ABD = amphotericin B deoxycholate; AE = adverse effects,

BIA points to a difference in the cost of using anidulafungin and ABD of R$100.61 (cost of treatment with anidulafungin = R$11,400.11; cost of ABD treatment = R$ 11,299.51). The additional cost to treat the entire demand in 5 years with anidulafungin would be approximately R$20 million, which has the best cost-effectiveness ratio (Table 4). As ABD was shown to be a dominating strategy with changes in the absolute response rate, probability of nephrotoxicity, and need for dialysis, BIA was estimated in these situations.

Table 4
Budgetary impact of the use of anidulafungin against ABD and sensitivity analysis of the variation in the absolute response rate and the probability of the existence of nephrotoxicity and the use of dialysis.

Year	Brazil, total population	IC new cases	Additional cost anidulafungin/ABD (R$)
2022	214,828,540	38,669	3,890,316.19
2023	216,284,269	38,931	3,916,677.90
2024	217,684,462	39,183	3,942,033.90
2025	219,029,093	39,425	3,966,383.74
2026	220,316,530	39,657	3,989,697.85
Total	-	-	19,705,109.58
Sensitivity analysis of the variation in the absolute response rate and the probability of the existence of nephrotoxicity and the use of dialysis
Year	Answer rate (R$)	Nephrotoxicity (R$)	Dialysis (R$)
2022	−26,475,625.75	−30,136,811.19	−16,083,149.26
2023	−26,655,030.85	−30,341,025.35	−16,192,132.48
2024	−26,827,591.66	−30,537,448.75	−16,296,958.00
2025	−26,993,304.96	−30,726,077.74	−16,397,623.87
2026	−27,151,969.63	−30,906,683.38	−16,494,007.90
Total	−134,103,522.84	−152,648,046.41	−81,463,871.51

• IC = invasive candidiasis.

In five years, the savings in favor of anidulafungin ranged from R$80 million, when compared to the growth of dialysis, to R$150 million to reduce the absolute rate of ABD response.

DISCUSSION

Different pharmacoeconomic analyses for these diseases and their pharmacotherapy have been performed in the international context⁸-¹⁰,¹², but, in the Brazilian scenario, they are nonexistent despite the fact that a public consultation on the incorporation of anidulafungin for the treatment of candidiasis is in progress.

Ou et al.⁸ analyzed the cost-effectiveness of caspofungin, micafungin, and anidulafungin versus non-echinocandins for C. albicans and non-albicans Candida species. Echinocandins, especially anidulafungin, are cost-effective for IC in Taiwan. Grau et al.¹⁰ compared the same echinocandins and fluconazole in the treatment of non-neutropenic adults with C/IC hospitalized in the ICU, in Spain. Anidulafungin was the most cost-effective treatment. Auzinger et al.¹² sought to develop a cost-effectiveness model from a UK perspective, analyzing the costs and outcomes of antifungal treatment for candidemia and IC based on the European Society of Clinical Microbiology and Infectious Disease guidelines. Anidulafungin was compared with caspofungin, micafungin, and fluconazole. The model included non-neutropenic patients aged ≥ 16 years old. Anidulafungin was cost-effective when compared to fluconazole for the treatment of C/IC, in addition to being more economical than the other echinocandins. In Australia, Neoh et al.⁹ investigated the cost-effectiveness of anidulafungin compared to fluconazole for the treatment of IC, where anidulafungin appears as a cost-effective option.

ABLC serves as a second-line option or salvage therapy for the treatment of systemic infections in patients who are refractory or intolerant to ABD or other antifungal agents, patients with renal failure or other contraindications²⁰,²¹. The data leading to the approval by the Food and Drug Administration (FDA), the US regulatory agency for the clinical use of ABL, were derived from data collected from 556 cases of invasive fungal infections, through an open method in refractory or intolerant to antifungal therapy²². Most of these patients had been previously exposed to ABD. Another important data source is support from the Collaborative Exchange of Antifungal Research (CLEAR) sector, which provides information on the renal efficacy and safety of ABD and ABLC from data of 3,514 patients who received the drug from 1996 to 2000 in 160 US institutions²³.

However, these data have limitations: the record is retrospective; collection was based on voluntary notification, with possible selection bias; the defined response criteria were lacking; and patient follow-up was limited. In addition, because ABLC is not used in first-line treatment, no data exist on the best rescue therapy. Thus, evidence of the use of ABLC is insufficient or nonexistent. To overcome these difficulties, the existing information was assumed for ABL. This hypothesis was based on proof of the response similarity of the two formulations¹⁸,²⁴-²⁹. The model conclusions should consider this restriction.

This study also has limitations that need to be discussed. Some of them are inherent to the modeling process, which can oversimplify the progression of the disease because of divergences from the real world, the use of more than one treatment, the care and hospitalizations with the complications of the disease, and the adverse effects of the treatment. The presence of Candida glabrata in up to 10% of patients that prevents the use of fluconazole due to therapeutic failure was not considered³⁰,³¹. Different international data sources served as a basis for estimating the values of transition probabilities, but, in the sensitivity analysis, such variables showed no impact on the results.

The unit costs were derived from SIGTAP and may have been underestimated. In this analysis, equal days of hospitalization were assumed for patients who used any of the technologies. The duration of admission, risk of readmission, and risk of complications could be longer, thus increasing the cost and duration of hospital care. BIA was carried out based on the product of the previous economic assessment. Consequently, all the limitations listed there also apply to this study.

CONCLUSION

The consensus of international scientific societies recommends echinocandins, including anidulafungin, as the first-line treatment for HF and candidemia in moderately to severely ill patients. Anidulafungin proved to be a cost-effective option for the first-line treatment of HF and candidemia. More vulnerable patients would benefit from this recognized safety, tolerability, and efficacy profile, while the health system would benefit from its incorporation.

ACKNOWLEDGMENTS

This article was financed by the Department of Management and Incorporation of Technologies and Innovation in Health (DGITIS/SCTIE/MS) and the Pan-American Health Organization (PAHO) in Brazil.

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Publication Dates

• Publication in this collection
  30 Jan 2023
• Date of issue
  2023

History

• Received
  9 Sept 2022
• Accepted
  13 Dec 2022