A Markov cohort model was constructed to assess the cost-utility of using caspofungin or fluconazole antifungal agents as empiric first-line therapy,i.e., in the absence of microbiology workup or while awaiting for culture and susceptibility data, for Ethiopian adult inpatients with IC/C. This study was carried out from the Ethiopian health system perspective over a lifetime horizon. Consistent with the health system perspective, we included direct medical costs such as drug acquisition cost, hospitalization costs, cost of diagnosis and monitoring tests. Primary outcomes were expected life years (LYs), quality-adjusted life years (QALYs), costs (US$ 2021), and the incremental cost-effectiveness ratio (ICER) expressed in US$ per QALY gained. The ICER was calculated as the difference in cost between the strategies divided by the difference in effectiveness (QALYs). QALYs were determined by multiplying the years lived in a given health state with the utility weights of that state [14]. Costs and QALYs were discounted at an annual rate of 3%, as recommended for LMICs [15]. Ethiopia has not established a cost-effectiveness threshold. The World Health Organization (WHO) recommends a cost-effectiveness threshold of 1-3 times GDP/capita [15]. However, in recent years, the use of this threshold has been widely questioned for a lack of scientific underpinnings to guide resource allocation decisions [16, 17]. Hence, we compared our ICER values against the recently recommended threshold of 50% of a country’s gross domestic product (GDP)/capita for LMICs [17]. Ethiopia's GDP per capita at the time of the study was US$952 [18]. The study was designed, conducted, and reported following the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement [19].
Treatment strategies
We compare three treatment strategies: 1) Caspofungin treatment followed by L-AmB (CASPO -> L-AmB): patient received intravenous caspofungin (loading dose 70 mg on day 1, then 50 mg daily maintenance dose for 14 days) and those who had experienced treatment failure were switched to an additional 14 days of L-AmB (3 mg/kg per day for an average weight of 70 kg); 2) Fluconazole treatment followed by caspofungin (FLU -> CASPO -> L-AmB): patient received fluconazole oral (800-mg loading dose, then 400 mg daily for 14 days) and those who had failed to respond to fluconazole were switched to caspofungin, with L-AmB being used as a rescue agent if infection persisted; 3) Fluconazole treatment followed by liposomal amphotericin B (L-AmB) (FLU -> L-AmB): patient took fluconazole oral (800-mg loading dose and 400 mg daily for 14 days thereafter) and if this treatment failed, L-AmB was used as the second-line therapy. In accordance with current practice in Ethiopia, we assumed that fluconazole and caspofungin would be prescribed for 14 days on average, regardless of their use as first- or second-line therapy. We consider the same treatment duration for L-AmB therapy. To evaluate each treatment separately, we assumed that patients who had failed therapy and/or those who had a recurrence would be managed with the same treatment as used for the previous episode. We assumed that patients were hospitalized throughout the treatment period and no patients had their medication dose titrated.
Model structure
A Markov cohort model was constructed based on current clinical practice and treatment outcomes of hospitalized IC/C patients receiving different types of antifungal therapy in Ethiopia. We built the model using TreeAge Software (TreeAge Software, Inc., Williamstown, MA). Figure 1 shows a simplified illustration of the model structure. A patient in hospital with IC/C could die from infection or be cured and transition to a healthy state, which is defined as the complete resolution of the infection (i.e. clinical and microbiological success) with no need for additional systemic antifungal therapy [20]. Patients who were first treated and cured could either stay healthy or develop IC/C again. If the first-line treatment failed, patients would be switched to second-line antifungal treatment (Fig 1B). All patients could die from causes unrelated to IC/C. The simulated population reflects the Ethiopian inpatient with a mean age of 39 years (informed by hospital data). All patients were followed in a 3-months time step (cycle length) over their life expectancy.
PARAMETER INPUTS
Model inputs including probabilities, utilities, and costs are reported in Table 1.
Probabilities
In the absence of local data, the literature was used to inform health state transitions. A meta-analysis by Millis et al (2009) reported that caspofungin is superior, with favorable treatment response in 76.1% of patients, as compared to 63% for fluconazole and 72.98% for L-AmB [21]. The attributable mortality associated with IC/C was 28.44% in patients who received fluconazole and 33.83% with caspofungin. Recurrent candidemia was found in 4.4% of patients [22] and we assumed the same infection recurrence rate for all treatment strategies. Life expectancy data from the WHO Global Health Observatory for Ethiopia was used to populate age-specific mortality unrelated to IC/C [23].
Table 1. Model parameter point estimate values and ranges
Parameter
|
Point estimate
|
Plausible Range
|
Distribution
|
Reference
|
Treatment efficacy (success rate, %)
|
|
|
|
|
|
Fluconazole
|
63.0
|
57.0 - 74.0
|
Beta
|
Mills et. al., 2009 [21]
|
|
Caspofungin
|
76.1
|
63.6 - 78.0
|
Beta
|
Mills et. al., 2009 [21]
|
|
L-AmB
|
72.9
|
66.4 - 76.0
|
Beta
|
Mills et. al., 2009 [21]
|
Mortality rate (%)
|
|
|
|
|
|
Fluconazole
|
28.4
|
16.6 - 31.4
|
Beta
|
Mills et. al., 2009 [21]
|
|
Caspofungin
|
33.8
|
26.4 - 34.2
|
Beta
|
Mills et. al., 2009 [21]
|
|
|
|
|
|
|
IC/C recurrence rate (%)
|
4.4
|
1.4 - 13.0
|
Beta
|
Ásmundsdóttir et. al., 2012; Muñoz et. al., 2016; Reboli et. al.,2007; Pappas et. al., 2007
[20, 22, 24, 25]
|
Utilities
|
|
|
|
|
|
Patient with IC/C
|
0.72
|
0.50 - 0.94
|
Beta
|
CEA Registry, Tufts Medical Center
|
|
Healthy or survivors
|
0.94
|
0.84 - 0.94
|
Beta
|
Granja et. al., 2004; Welie et. al., 2020 [26, 27]
|
Costs (US$)
|
|
|
|
|
|
Loading dose cost
|
|
|
|
|
|
|
Fluconazole 800mg per day
|
$3
|
$2 - 5
|
Gamma
|
TASH and MCM
|
|
|
Caspofungin 70mg per day
|
$179
|
$150 - 200
|
Gamma
|
MCM
|
|
|
L-AmB (3 mg/kg per day for an average weight of 70 kg)
|
$198
|
$190 - 215
|
Gamma
|
TASH and MCM
|
|
Maintenance dose
|
|
|
|
|
|
|
Fluconazole 400mg per day
|
$17
|
$15 - 30
|
Gamma
|
TASH and MCM
|
|
|
Caspofungin 50mg per day
|
$2,322
|
$2,000 - 2,500
|
Gamma
|
MCM
|
|
|
L-AmB (3 mg/kg per day for an average weight of 70 kg)
|
$2,574
|
$500 - 2,700
|
Gamma
|
TASH and MCM
|
|
Hospitalization cost per day
|
$5
|
$1 - 35
|
Gamma
|
TASH and MCM
|
|
Diagnostic and monitoring costs
|
$76
|
$50 - 100
|
Gamma
|
TASH and MCM
|
TASH: Tikur Anbesa Specialized Hospital; MCM: Myung Sung Christian Medical General Hospital
Utilities
We derived utilities from the literature because local utility values for these patient populations were not available. Because Ethiopia's general population mean utility is comparable to that of high-income nations [26], we used utilities from Western countries. The utility score for patients with IC/C (0.72) was extracted from the catalogue of preference scores 1997–2018 from the Cost-Effectiveness Analysis Registry of the Tufts Medical Center (https://cevr.tuftsmedicalcenter.org/databases/cea-registry). We assumed that individuals who were treated and cured from the disease would have the same utility weight as the general Ethiopian population (0.94) [26], which is in agreement with the previous study which showed no major difference in utility weights between those population groups [27].
Cost
All cost data were obtained from Tikur Anbessa Specialized Hospital (TASH) and/or Myung Sung Christian Medical General Hospital (MCM) records in Addis Ababa, Ethiopia. The mean total medication costs per patient were $20 for fluconazole ($3 for the loading dose and $17 for the maintenance dose), $2,501 for caspofungin ($179 for loading dose and $2,322 for maintenance dose), and $2,772 for L-AmB. We estimated hospitalization cost per day of $5 and the average cost of diagnosis and monitoring tests (such as chest X-ray, computed tomography scan, complete blood count, renal function test, liver function test, electrolyte test) was $76 per patient. All costs are expressed in 2021 US$ (1US$=43.3 Ethiopian Birr) [28].
ANALYSIS
In the base-case analysis, we consider hypothetical IC/C patients aged 39 years (based on the mean age of adult inpatients at TASH.
We performed deterministic and probabilistic sensitivity analyses to assess the impact of parameter uncertainties and the robustness of our analysis. In the deterministic sensitivity analysis, we assessed parameter value uncertainty by varying each input variable within a plausible range of values presented in Table 1. We also perform probabilistic sensitivity analysis, running 10,000 Monte Carlo simulations, in which all input variables were allowed to vary simultaneously according to the predefined probability distribution (i.e., gamma distributions for costs, and beta distributions for probabilities and utilities).