A cost-effectiveness analysis of the use of oral ibrexafungerp versus fluconazole for acute vulvovaginal candidiasis in the UK NHS primary care service.

BACKGROUND: Vulvovaginal Candidiasis (VVC) is a fungal infection causing inflammation of the vagina and/or the vulva. Symptoms include itching, irritation, and discharge. VVC presents commonly across primary care and, despite its mild symptoms, carries psychological burden and has a significant impact on women's quality of life. UK guidelines support treatment via oral or topical azole antifungal agents. Recent evidence attests to the superiority of novel non-azole antifungals. Thus, rigorous financial assessment of both antifungals is necessary for optimal VVC treatment allocation in UK primary care. AIM: To evaluate the cost-effectiveness of ibrexafungerp against the gold standard fluconazole as first-line treatment of VVC within the NHS. METHOD: A systematic review on the efficacy of ibrexafungerp and fluconazole in acute VVC was conducted. Cost-effectiveness analysis was initiated using health outcome data from the DOVE trial, a Phase 2 RCT. Costs in pound sterling were ascertained in monetary units, and effectiveness determined as reduced need for follow-up medication. RESULTS: An incremental cost-effectiveness ratio of £2185.74 was determined. This suggests oral ibrexafungerp being largely more costly yet slightly more effective than fluconazole, and thus has unfavourable net benefit. Two sensitivity analyses were conducted considering follow-up medication combination and market price, which provided confidence in the calculated cost-effectiveness ratio. CONCLUSION: This analysis highlights fluconazole's cost-effectiveness in current UK guidelines and favourability.

Leave no one behind: response to new evidence and guidelines for the management of cryptococcal meningitis in low-income and middle-income countries.

In 2018, WHO issued guidelines for the diagnosis, prevention, and management of HIV-related cryptococcal disease. Two strategies are recommended to reduce the high mortality associated with HIV-related cryptococcal meningitis in low-income and middle-income countries (LMICs): optimised combination therapies for confirmed meningitis cases and cryptococcal antigen screening programmes for ambulatory people living with HIV who access care. WHO's preferred therapy for the treatment of HIV-related cryptococcal meningitis in LMICs is 1 week of amphotericin B plus flucytosine, and the alternative therapy is 2 weeks of fluconazole plus flucytosine. In the ACTA trial, 1-week (short course) amphotericin B plus flucytosine resulted in a 10-week mortality of 24% (95% CI -16 to 32) and 2 weeks of fluconazole and flucytosine resulted in a 10-week mortality of 35% (95% CI -29 to 41). However, with widely used fluconazole monotherapy, mortality because of HIV-related cryptococcal meningitis is approximately 70% in many African LMIC settings. Therefore, the potential to transform the management of HIV-related cryptococcal meningitis in resource-limited settings is substantial. Sustainable access to essential medicines, including flucytosine and amphotericin B, in LMICs is paramount and the focus of this Personal View.

Rapid species identification of Candida directly from blood culture broths by Sepsityper-MALDI-TOF mass spectrometry: impact on antifungal therapy.

Rapid identification of Candida species facilitates pathogen-directed therapy with either fluconazole or an echinocandin. METHOD: We applied Sepsityper matrix-assisted laser desorption ionisation time of flight mass spectrometry (MALDI-TOF-MS) technology on positive blood culture broths for rapid species identification. RESULTS: Of the 74 patients with candidaemia, 25 had the species identified on the day of the positive blood culture directly from the broth (rapid identification group) while the remaining 49 had the species identified from culture (conventional identification group). Three (13.6%) out of 22 treated patients in the rapid identification group received echinocandin compared to 20/45 (44.4%) in the conventional identification group. The appropriateness of therapy was 90.9% in the rapid identification group and 62.2% in the conventional identification group (p = 0.01). Cost savings were more than £10,000 in the first three days of treatment. CONCLUSION: Sepsityper-MALDI-TOF-MS is a useful tool in supporting antifungal stewardship programmes.

Cost-effectiveness of posaconazole in private and public Brazilian hospitals.

BACKGROUND: Posaconazole is used for the prophylaxis of invasive fungal disease (IFD). Previous studies have shown it to be cost-effective compared to fluconazole/itraconazole. However, posaconazole has never been economically evaluated in developing countries. AIMS: The aim of the present study was to perform a cost-effectiveness analysis of posaconazole compared to fluconazole in public (SUS) and private hospitals (PHS) in Brazil. METHODS: A cost-effectiveness simulation was conducted on the basis of a pivotal study on the use of posaconazole in acute myeloid leukemia (AML) patients, adjusting the costs to Brazilian data. RESULTS: A pharmacoeconomic analysis was performed on a hypothetical sample of 100 patients in each drug group. The total cost of posaconazole use alone was USD$ 220,656.31, whereas that for fluconazole was USD$ 83,875.00. Our results showed that patients with IFD remain hospitalized for an additional 12 days, at an average cost of USD$ 850.85 per patient per day. The total money spent by PHS for 100 patients for 100 days was USD$ 342,318.00 for the posaconazole group and USD$ 302,039.00 for the fluconazole group. An analysis of sensitivity (10%) revealed no intergroup difference. CONCLUSIONS: In Brazil posaconazole is cost-effective, and should be considered for the prophylaxis of patients with AMD/myelodysplasia (AML/MDS) undergoing chemotherapy.

Cost-effectiveness of de-escalation from micafungin versus escalation from fluconazole for invasive candidiasis in China.

AIMS: Guidelines on treating invasive candidiasis recommend initial treatment with a broad-spectrum echinocandin (e.g. micafungin), then switching to fluconazole if isolates prove sensitive (de-escalation strategy). This study aimed to evaluate the cost-effectiveness of de-escalation from micafungin vs escalation from fluconazole from a Chinese public payers perspective. MATERIALS AND METHODS: Cost-effectiveness was estimated using a decision analytic model, in which patients begin treatment with fluconazole 400 mg/day (escalation) or micafungin 100 mg/day (de-escalation). From Day 3, when susceptibility results are available, patients are treated with either fluconazole (if isolates are fluconazole-sensitive/dose-dependent) or micafungin (if isolates are resistant). The total duration of (appropriate) treatment is 14 days. Model inputs are early (Day 3) and end-of-treatment mortality rates, treatment success rates, and health resource utilization. Model outputs are costs of health resource utilization over 42 days, incremental cost per life-year, and incremental cost per quality-adjusted life-year (QALY) over a lifetime horizon. RESULTS: In the base-case analysis, the de-escalation strategy was associated with longer survival and higher treatment success rates compared with escalation, at a lower overall cost (-¥1,154; -175 United States Dollars). Life-years and QALYs were also better with de-escalation. Thus, this strategy dominated the escalation strategy for all outcomes. In a probabilistic sensitivity analysis, 99% of 10,000 simulations were below the very cost-effective threshold (1 × gross domestic product). LIMITATIONS: The main limitation of the study was the lack of real-world input data for clinical outcomes on treatment with micafungin in China; data from other countries were included in the model. CONCLUSION: A de-escalation strategy is cost-saving from the Chinese public health payer perspective compared with escalation. It improves outcomes and reduces costs to the health system by reducing hospitalization, due to an increase in the proportion of patients receiving appropriate treatment.

Cost-effectiveness of posaconazole tablets versus fluconazole as prophylaxis for invasive fungal diseases in patients with graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: The cost-effectiveness of posaconazole oral suspension versus fluconazole capsules for the prophylaxis of invasive fungal diseases (IFDs) in immunosuppressed allogeneic hematopoietic stem cell transplantation (HSCT) recipients has already been proven. Now, a new solid oral tablet formulation for posaconazole has been developed with improved bioavailability, allowing a reduced daily dosage that can be taken independently of food intake. However, the efficacy of this new formulation should be evaluated since it is associated with a higher cost than the posaconazole oral suspension. OBJECTIVES: To evaluate the cost-effectiveness of solid oral tablets of posaconazole versus fluconazole capsules for the prophylaxis of IFDs in allogeneic HSCT recipients with graft-versus-host disease (GVHD) in Spain. METHODOLOGY: A mathematical model comparing the efficacy and costs of posaconazole versus fluconazole was adapted to the Spanish National Healthcare System. Clinical data were obtained from the pivotal clinical trial of posaconazole oral suspension for allogeneic HSCT recipients, while pharmacological costs and use of resources were obtained from national sources. Deterministic and probabilistic sensitivity analyses (PSA), as well as two alternative scenarios, were run to evaluate the robustness of the results under varying input values. RESULTS: Posaconazole tablets reduced the number of IFD events and enhanced overall survival, while maintaining a controlled budget. When compared to fluconazole, it was found to be a cost-effective alternative, with an incremental cost-effectiveness ratio of €13,193/life years gained. The PSA showed that posaconazole remained cost-effective in 74.6% of the cases, while alternatives scenarios yielded similar results as the base case. CONCLUSIONS: Posaconazole tablets are a cost-effective alternative to fluconazole and may show better results than the oral suspension formulation.

Fluconazole versus mould-active triazoles for primary antifungal prophylaxis in adult patients with acute lymphoblastic leukemia: clinical outcome and cost-effectiveness analysis.

This study evaluated the clinical and cost-effectiveness of prophylactic use of fluconazole versus mould-active triazoles (voriconazole and posaconazole) in adult patients with acute lymphoblastic leukemia (ALL). A decision analytical model was developed with inputs from a 7-year retrospective study (2009-2016) of 103 consecutive adult patients with ALL who received antifungal prophylaxis. Information on the administration of antifungal agents, clinical outcomes, and costs were collected. One-way sensitivity analyses and probabilistic sensitivity analysis were performed. The mould-active triazoles group was associated with higher life-years (3.71 vs 3.59) and lower total costs (US$4886 vs US$5722) per patient compared with fluconazole. One-way sensitivity analyses revealed that varying all of the key variables in the model did not affect the robustness of the results. Probabilistic sensitivity analysis demonstrated that mould-active triazoles had a probability of 77.1 and 90.1% of providing a dominant and cost-effective option relative to fluconazole, respectively. Mould-active triazoles should be regarded as preferable to fluconazole as the first-line prophylactic for adult patients with ALL accompanied by uncommon severe vinca alkaloid-induced neurotoxicity. However, the results reported here should be interpreted with caution owing to the observational nature of the data.

Cost Effectiveness of Candida Polymerase Chain Reaction Detection and Empirical Antifungal Treatment among Patients with Suspected Fungal Peritonitis in the Intensive Care Unit.

BACKGROUND: Mortality from intra-abdominal candidiasis in intensive care units (ICUs) is high. It takes many days for peritoneal-fluid fungal culture to become positive, and the recommended empirical antifungal therapy involves excessive costs. Polymerase chain reaction (PCR) should produce results more rapidly than fungal culture. OBJECTIVES: To perform a cost-effectiveness analysis of the combination of several diagnostic and therapeutic strategies to manage Candida peritonitis in non-neutropenic adult patients in ICUs. METHODS: We constructed a decision tree model to evaluate the cost effectiveness. Cost and effectiveness were taken into account in a 1-year time horizon and from the French National Health Insurance perspective. Six strategies were compared: fluconazole or echinocandin as an empirical therapy, plus diagnosis by fungal culture or detection by PCR of all Candida species, or use of PCR to detect most fluconazole-resistant Candida species (i.e., Candida krusei and Candida glabrata). RESULTS: The use of fluconazole empirical treatment and PCR to detect all Candida species is more cost effective than using fluconazole empirical treatment without PCR (incremental cost-effectiveness ratio of €40,055/quality-adjusted life-year). Empirical treatment with echinocandin plus PCR to detect C. krusei and C. glabrata is the most effective strategy, but has an incremental cost-effectiveness ratio of €93,776/quality-adjusted life-year. If the cost of echinocandin decreases, then strategies involving PCR plus empirical echinocandin become more cost-effective. CONCLUSIONS: Detection by PCR of all Candida species and of most fluconazole-resistant Candida species could improve the cost-effectiveness of fluconazole and echinocandin given to non-neutropenic patients with suspected peritoneal candidiasis in ICUs.

Choosing Optimal Antifungal Agents To Prevent Fungal Infections in Nonneutropenic Critically Ill Patients: Trial Sequential Analysis, Network Meta-analysis, and Pharmacoeconomic Analysis.

The use of antifungal interventions in critically ill patients prior to invasive fungal infection (IFI) being microbiologically confirmed and the preferred drug are still controversial. A systematic literature search was performed to identify randomized controlled trials (RCTs) that compared untargeted antifungal treatments applied to nonneutropenic critically ill patients. The primary outcomes were all-cause mortality and proven IFI rates. A random-effects model was used with trial sequential analyses (TSA), a network meta-analysis (NMA) was conducted to obtain indirect evidence, and a cost-effectiveness analysis using a decision-analytic model was completed from the patient perspective over a lifetime horizon. In total, 19 RCTs involving 2,556 patients (7 interventions) were included. Untargeted antifungal treatment did not significantly decrease the incidence of all-cause mortality (odds ratio [OR] = 0.89, 95% confidence interval [95%CI] = 0.70 to 1.14), but it did reduce the incidence of proven IFI (OR = 0.45, 95%CI = 0.29 to 0.71) relative to placebo/no intervention. The TSA showed that there was sufficient evidence supporting these findings. In the NMA, the only significant difference found for both primary outcomes was between fluconazole and placebo/no intervention in preventing proven IFI (OR = 0.35, 95%CI = 0.19 to 0.65). Based on drug and hospital costs in China, the incremental cost-effectiveness ratios per life-year saved for fluconazole, caspofungin, and micafungin relative to placebo/no intervention corresponded to US$889, US$9,994, and US$10,351, respectively. Untargeted antifungal treatment significantly reduced proven IFI rates in nonneutropenic critically ill patients but with no mortality benefits relative to placebo/no intervention. Among the well-tolerated antifungals, fluconazole remains the only one that is effective for IFI prevention and significantly cheaper than echinocandins.

Cost-Effectiveness of Posaconazole Tablets for Invasive Fungal Infections Prevention in Acute Myelogenous Leukemia or Myelodysplastic Syndrome Patients in Spain.

INTRODUCTION: Posaconazole is superior to fluconazole (FLU) and itraconazole (ITRA) in the prevention of invasive fungal diseases (IFDs) in neutropenic patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). A new tablet formulation of posaconazole with improved pharmacokinetic and pharmacodynamic properties compared to posaconazole oral solution has recently been approved. The objective of this study is to estimate the cost-effectiveness of the newly developed posaconazole tablets versus FLU oral suspension or ITRA oral solution for preventing IFDs in high-risk neutropenic patients with AML or MDS and from the perspective of the Spanish National Health System (NHS). METHODS: A previously validated economic model was used. The probabilities of experiencing an IFD, an IFD-related death or death from other causes over 100 days were based on clinical trial data and input into a decision tree. Surviving patients were entered into a Markov model to calculate total costs, number of IFDs and number of life-years gained per patient over a lifetime horizon in each disease and treatment group. Two health states, alive and dead, were considered. Health effects were discounted using a rate of 3%. Univariate and probabilistic sensitivity analyses were conducted. RESULTS: During the first 100 days, posaconazole tablets were associated with a lower risk of IFDs (0.046 vs. 0.111), longer life expectancy (2.92 vs. 2.69 years) and lower total costs (€5906.06 vs. €7847.20 per patient) over the patients' lifetimes compared to FLU or ITRA treatments. Thus, posaconazole tablets were more effective and less costly than FLU or ITRA. Probabilistic sensitivity analysis indicated that there was a 79.9% probability of posaconazole tablets being cost-saving compared to FLU or ITRA. CONCLUSION: From the Spanish NHS perspective, posaconazole tablets are cost-effective compared to FLU or ITRA in AML or MSD patients with chemotherapy-induced neutropenia and at high risk for IFDs. FUNDING: MSD Sharp & Dohme.