- Email: [email protected]
Posaconazole vs. voriconazole in the prevention of invasive fungal diseases in patients with haematological malignancies: A retrospective study
+ Models
MYCMED-742; No. of Pages 5 Journal de Mycologie Médicale (2017) xxx, xxx—xxx
Available online at
ScienceDirect www.sciencedirect.com
ORIGINAL ARTICLE/ARTICLE ORIGINAL
Posaconazole vs. voriconazole in the prevention of invasive fungal diseases in patients with haematological malignancies: A retrospective study L. Tang a,b, X.-F. Yang a,b, M. Qiao a,b, L. Zhang a,b, X.-W. Tang a,b, H.-Y. Qiu a,b, D.-P. Wu a,b, A.-N. Sun a,b,* a b
Department of hematology, the First Affiliated Hospital of Soochow University, Suzhou, China Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
Received 12 September 2017; received in revised form 6 November 2017; accepted 13 November 2017
KEYWORDS Posaconazole; Voriconazole; IFDs
Summary Background. — Posaconazole is superior to fluconazole or itraconazole in preventing invasive fungal diseases (IFDs) in patients with haematological malignancies; however, there have been reports of the comparing posaconazole and voriconazole. Methods. — This single-centre, retrospective study in China enrolled AML, ALL and MDS patients, among others. Prophylaxis with posaconazole or voriconazole was administered for patients recovering from neutropenia or who had achieved complete remission. The primary emphasis was proven, probable, or possible IFDs during treatment. The cost-effectiveness, the proportion of adverse events and systemic antifungal treatment were the secondary emphasis. Results. — A total of 164 patients were recruited to receive posaconazole (n = 81) or voriconazole (n = 83). The incidence rates of proven, probable or possible IFD were 2.46% (2/81) and 4.82% (4/83) in the posaconazole group and voriconazole groups, respectively (P > 0.05). Only one patients experienced adverse events on posaconazole, while eleven patients experienced such events on voriconazole (P = 0.003). Patients receiving posaconazole or voriconazole had similar proportions of systemic antifungal treatment: 18.52% (15/81) in the posaconazole group and 16.87% (14/83) in the voriconazole group (P > 0.05). In the cost-effectiveness analysis, the prognosis of the two groups was close, but the drug acquisition costs of posaconazole were higher than those of voriconazole (P = 0.021).
* Corresponding author at: The First Affiliated Hospital of Soochow University, Jiang Su, China. E-mail address: [email protected] (A.N. Sun). https://doi.org/10.1016/j.mycmed.2017.11.003 1156-5233/# 2017 Published by Elsevier Masson SAS.
Please cite this article in press as: Tang L, et al. Posaconazole vs. voriconazole in the prevention of invasive fungal diseases in patients with haematological malignancies: A retrospective study. Journal De Mycologie Médicale (2018), https://doi.org/10.1016/j.mycmed.2017.11.003
+ Models
MYCMED-742; No. of Pages 5
2
L. Tang et al. Conclusion. — Posaconazole and voriconazole have the same prophylactic effect against IFDs in high-risk neutropenic Chinese patients. However, the safety of posaconazole is superior to that of voriconazole, while in terms of cost-effectiveness, voriconazole has an advantage over posaconazole. # 2017 Published by Elsevier Masson SAS.
Introduction Invasive fungal diseases (IFDs) are diseases in which fungi invade the body and reproduce in the tissues, organs or blood, ultimately causing inflammation and tissue injury [1]. The incidence of IFDs has steadily increased in recent years in patients with haematological malignancies, because of the development of chemotherapy regimes and transplantations. IFDs are an important threat to patients with haematological malignancies and are associated with significant morbidity and mortality. Patients who undergo induction chemotherapy and haematopoietic stem cell transplantation (HSCT) are at high risk of developing IFDs. There are no specific clinical manifestations during the early stage of IFDs, and the limited curative effect and adverse reactions of antifungal drugs have yet to be resolved. Therefore, prophylaxis against IFDs is particularly important. Posaconazole is a broad-spectrum oral triazole, and is effective as a prophylaxis in reducing IFDs in high-risk patients [2]. The aim of this study was to compare the efficacy, safety and cost-effectiveness of posaconazole and voriconazole in the prevention of IFDs in Chinese patients with haematological malignancies, who received chemotherapy or haematopoietic stem cell transplantation.
Patients and methods Patients Patients were collected from the first affiliated hospital of Soochow University from January 2016—April 2017 in either general wards or transplant purification warehouses with posaconazole or voriconazole treatment for preventing IFDs. All of the patients either had persistent neutropenia (absolute neutrophil count < 0.5 109/L) or were expected to develop neutropenia in 3—5 days. Patients received standard chemotherapy, intensive chemotherapy or HSCT. All patients received posaconazole oral suspension (40 mg/mL) 200 mg, 3 times/day, or voriconazole 200 mg, 2 times/day. Patients were excluded if they had an electrolyte imbalance, severe renal insufficiency, liver dysfunction, or serious unstable cardiovascular or central nervous system abnormality before using posaconazole or voriconazole. Patients using other antifungal drugs for preventing IFDs were also excluded from the study.
Efficacy evaluation All patients were monitored carefully for any evidence of IFDs at the beginning and the end of the prophylaxis. Comprehensive surveillance included high-resolution chest computed tomography, culture of associated tissues or
samples and Aspergillus galactomannan assay for patients developing any signs or symptoms of infection during the treatment phase. The primary emphasis was the incidence of proven, probable, or possible diagnosis of IFDs during treatment, according to the European Organization for the Research and Treatment of Cancer and the Mycoses Study Group. Proven or probable IFDs were defined as invasive fungal infection breakthrough [1]. We also recorded the drug acquisition costs of posaconazole and voriconazole during the prevention of IFDs. The cost-effectiveness, the proportion of adverse events and systemic antifungal treatment were the secondary emphases.
Safety evaluation All adverse events were recorded and assessed according to the Common Toxicity Criteria grading system of the National Cancer Institute [3]. Important adverse events were defined as those needing medical intervention to change the treatment protocol.
Statistical analysis Data are mainly presented as medians and (ranges) and counts and (percentages). Comparisons between categorical variables were performed by Fisher’s exact test or the Chi2 test; for continuous variables, Student’s t-test or analysis of variance was used. The survival distribution function was estimated using the Kaplan—Meier product-limit method. P < 0.05 indicated statistically significant differences.
Results Patients’ characteristics A total of 164 patients were recruited to receive either posaconazole (n = 81) or voriconazole (n = 83). The two groups had similar baseline characteristics in terms of demographic data, underlying diseases and neutropenia duration (Table 1).
IFDs breakthrough rates and systemic antifungal therapy During the treatment phase, the average days of drug administration were 19.49 days and 14.81 days in the posaconazole group and voriconazole groups, respectively (P > 0.05). There were no proven diagnoses in the groups, and each had one probable pulmonary fungal infection who died following Ambisome antifungal therapy. The breakthrough rates of
Please cite this article in press as: Tang L, et al. Posaconazole vs. voriconazole in the prevention of invasive fungal diseases in patients with haematological malignancies: A retrospective study. Journal De Mycologie Médicale (2018), https://doi.org/10.1016/j.mycmed.2017.11.003
+ Models
MYCMED-742; No. of Pages 5
Posaconazole vs. voriconazole in the prevention of invasive fungal diseases Table 1
3
Clinical characteristics of the patients. Posaconazole Voriconazole P (n = 81) (n = 83) value
Age, year Mean SD Median (range) Sex, n (%) Male Female Underlying diseases AML ALL MDS SAA HAL NHL MM Therapy methods Chemotherapy HSCT Total duration of neutropenia in treatment phase, days Median (range) Mean SD
35.28 1.83 32 (10 78)
37.19 1.58 0.180 37 (5 70)
47 (58.02%) 34 (41.98%)
47 (56.63%) 36 (43.37%)
0.317
29 (35.80%) 30 (37.04%) 11 (13.58%) 6 (7.41%) 0 2 (2.47%) 3 (3.70%)
53 (63.86%) 24 (28.92%) 2 (2.41%) 2 (2.41%) 2 (2.41%) 0 0
0.352
33 (40.74%) 48 (59.26%)
64 (77.11%) 19 (22.89%)
0.655
14 (0 51) 14.85 1.16
13 (0 44) 0.121 13.46 0.88
Figure 1 Kaplan—Meier analysis of overall survival between the posaconazole group and the voriconazole group (P = 0.688).
AML: acute myelogenous leukaemia; ALL: acute lymphoblastic leukaemia; MDS: myelodysplastic syndrome; SAA: severe aplastic anaemia; HAL: hybrid acute leukaemia; NHL: non-Hodgkin’s lymphoma; MM: multiple myeloma; SD: standard deviation; HSCT: haematopoietic stem cell transplantation.
IFDs were 1.23% (posaconazole) vs. 1.20% (voriconazole) (P > 0.05). There were 15 patients in the posaconazole group and 14 in the voriconazole group receiving amphotericin B or caspofungin as systemic antifungal therapy, after they developed symptoms of IFDs (P > 0.05).
Figure 2 Results of follow-up between the posaconazole group and the voriconazole group. A total of 10 people died in each group, with no obvious statistical significance.
Safety
collected (due to various reasons). These findings indicate that the costs of preventing IFDs in the posaconazole group were significantly higher than that in the voriconazole group.
Adverse events were comparable between groups. Twelve serious adverse events were reported. One patient (1.23%) had a gastrointestinal reaction in the posaconazole group; one case of akoasm (1.20%), two cases of visual hallucination (2.41%) and eight cases of liver dysfunction (9.64%) were noted in the voriconazole group. There were no instances of renal impairments or long QTc intervals, among other similar complication. The entirety of adverse events in the posaconazole group compared with the voriconazole group (1 vs. 11 patients, P = 0.003), indicated posaconazole was obviously safer than voriconazole in the prevention of IFDs.
Cost of antifungal prophylaxis During the treatment phase, the average consumption on drug acquisition costs were 16,169.63 760.36 (4980 29,880 RMB) in the posaconazole group, and 13,062.65 692.95 (3900 27,300 RMB) in the voriconazole group (P = 0.021). The costs of treating IFDs were not
Follow-up Followed-up extended to May 2017; 38 patients failed to follow-up. The overall survival rates of the two groups were not obviously different (Fig. 1). Twenty patients out of 126 died, with ten patients dead in each group. There were two cases (3.70%) of infection-related death in the posaconazole group and one case (1.92%) in the voriconazole group (P > 0.05) (Fig. 2). There were 15 cases of aGVHD in HSCT patients, a condition that can be controlled by anti-rejection treatments: 11/48 (22.92%) in the posaconazole group vs. 4/ 19 (21.05%) in the voriconazole group (P = 0.574).
Discussion In recent years, a number of clinical trials have shown that patients with haematological malignancies who used
Please cite this article in press as: Tang L, et al. Posaconazole vs. voriconazole in the prevention of invasive fungal diseases in patients with haematological malignancies: A retrospective study. Journal De Mycologie Médicale (2018), https://doi.org/10.1016/j.mycmed.2017.11.003
+ Models
MYCMED-742; No. of Pages 5
4
L. Tang et al.
posaconazole for preventing IFDs were more effectively treated than those using fluconazole or itraconazole [4—6], but there have been few studies comparing posaconazole and voriconazole. Posaconazole and voriconazole are both newgeneration triazole broad-spectrum antifungal drugs. Posaconazole interferes with fungal cytochrome P450 enzyme synthesis and then further inhibits fungal cell wall synthesis of ergosterol and has antimicrobial effects against Candida, Aspergillus species, Cryptococcus neoformans, and bacteria, such as sickle-shaped bacteria [7]. Voriconazole inhibitis ergosterol biosynthesis of the P450 element 14-alpha sterol to its methylated form, thus inhibiting ergosterol biosynthesis and playing antifungal activities against Candida, Aspergillus species, genera of sickle-shaped bacteria, Cryptococcus yeast, other bacteria and other pathogenic fungi, with broad-spectrum antimicrobial effects [8]. The IDSA recommends that during chemotherapy or transplantation in patients with haematological malignancies, posaconazole should be administered as a first-line antimicrobial for preventing IFDs, with voriconazole can be as a secondary treatment [9]. However, in recent years, after chemotherapy or transplantation, the incidence of Candida infections fell, while Aspergillus and other fungal infection rates rose [10]. Voriconazole has more obvious resistance to Aspergillus fungus activity: therefore, the usage of voriconazole in haematological malignancies after chemotherapy or transplantation for preventing IFDs in China has increased years by years. This study included people with haematological malignancies undergoing chemotherapy and haematopoietic stem cell transplantation. Posaconazole and voriconazole exhibited no obvious differences in terms of curative effect for preventing IFDs. However, in this study, the posaconazole group exhibited only one case of gastrointestinal reaction (1.23%), lower than in an international report [11], one case of akoasm (1.20%), two cases of visual hallucinations (2.41%) and eight cases of liver dysfunctions (9.64%) in the voriconazole group. However, because of the presence of fewer samples, the ratios are lower than previously reported [12]. Regarding adverse events, on the whole, posaconazole was associated with significantly fewer events than voriconazole; thus, safety was higher than that of voriconazole. In clinical setting, cost-effective analysis is the most common method of valuating economics by far, and the cost-effective ratio is the commonly used method (the average cost per unit effects need: smaller cost-effective ratios indicate more efficiency). Compared with fluconazole or itraconazole, posaconazole has good economic benefit [13,14], posaconazole to be more efficacious and less expensive than standard azole agents [15]. However, there are fewer reports comparing posaconazole and voriconazole. The prices of posaconazole at home and abroad are higher: therefore, the expense of using posaconazole in this study was obviously higher than the price of voriconazole, as indicated by Antosz et al. [16] are the same. In this study, the effects of the two groups in the prevention of IFDs were the same, and there was no obvious difference in systemic antifungal treatment, but the drug costs of the preventing IFDs with voriconazole are lower than the costs with posaconazole. Therefore, in the cost-effectiveness analysis, voriconazole is superior to posaconazole.
Conclusion Posaconazole and voriconazole have favourable clinical efficacy in the prevention of IFDs. However, during the voriconazole treatment period for the prevention of IFDs, the possibilities of visual impairment and other adverse events (such as abnormal liver function) still need to be considered. We should strengthen the detection of drug concentration and actively adjust the dosage of drugs to avoid adverse drug reactions. The appropriate antifungal agents were also selected according to the different strains of drug-resistant strains. Posaconazole has better safety and preferable tolerance for patients with chemotherapy or transplantation. However, the drug costs of posaconazole are higher than those of voriconazole; therefore, the costeffectiveness of voriconazole is superior to that of posaconazole. Therefore, we recommend that patients who are young and have good liver and kidney function use voriconazole for the prevention of IFDs and that patients who are older have more complications and more feasible infection factors use posaconazole for the prevention of IFDs. As the drug costs of posaconazole are still higher domestically, it is used less, and this study was only a single-centre study. Further, multicentre controlled studies are needed to expand the sample size.
Disclosure of interest The authors declare that they have no competing interest.
References [1] De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 2008;46:1813—21. [2] Cornely OA, Ullmann AJ. Numbers needed to treat with posaconazole prophylaxis to prevent invasive fungal infection and death. Clin Infect Dis 2008;46:1626—7. [3] Trotti A, Byhardt R, Stetz J, Gwede C, Corn B, Fu K, et al. Common toxicity criteria: version 2.0. An improved reference for grading the acute effects of cancer treatment: impact on radiotherapy. Int J Radiat Oncol Biol Phys 2000;47:13—47. [4] Döring M, Eikemeier M, Cabanillas Stanchi KM, Hartmann U, Ebinger M, Schwarze CP, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. New Eng J Med 2007;356:348—59. [5] Ullmann AJ, Lipton JH, Vesole DH, Chandrasekar P, Langston A, Tarantolo SR, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. New Eng J Med 2007;356:335—47. [6] Shen Y, Huang XJ, Wang JX, Jin J, Hu JD, Yu K, et al. Posaconazole vs. fluconazole as invasive fungal infection prophylaxis in China: a multicenter, randomized, open-label study. Int J Clin Pharmacol Ther 2013;51:738—45. [7] Aperis G, Alivanis P. Posaconazole: a new antifungal weapon. Rev Recent Clin Trials 2011;6:204—19. [8] Mitra A, Savant V, Aralikatti A, Dean S, Shah S. The use of voriconazole in the treatment of cylindrocarpon keratomycosis. Cornea 2009;28:217—22.
Please cite this article in press as: Tang L, et al. Posaconazole vs. voriconazole in the prevention of invasive fungal diseases in patients with haematological malignancies: A retrospective study. Journal De Mycologie Médicale (2018), https://doi.org/10.1016/j.mycmed.2017.11.003
+ Models
MYCMED-742; No. of Pages 5
Posaconazole vs. voriconazole in the prevention of invasive fungal diseases [9] Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenia patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2011;52:e56—93. [10] Neofytos D, Horn D, Anaissie E, Steinbach W, Olyaei A, Fishman J, et al. Epidemiology and outcome of invasive fun#infection in adult hematopoietic stem cell transplant recipients: analysis of multicenter Prospective Antifungal Therapy (PATH) Alliance registry. Clin Infect Dis 2009;48:265—73. [11] Raad II, Graybill JR, Bustamante AB, Cornely OA, Gaona-Flores V, Afif C, et al. Safety of long-term oral term oral posaconazole use in the treatment of refractory invasive fungal invasive fungal infections. Clin Infect Dis 2006;42:1726—34. [12] Hoffman HL, Rathbun RC. Review of the safety and efficacy of voriconazole. Expert Opin Investing Drugs 2002;11:409—29. [13] Jansen JP, O’Sullivan AK, Lugtenburg E, Span LF, Janssen JJ, Stam WB. Economic evaluation of posaconazole versus fluco-
5
nazole prophylaxis in patients with graft-versus-host disease (GVHD) in the Netherlands. Ann Hematol 2010;89:919—26. [14] O’Sullivan AK, Weinstein MC, Pandya A, Thompson D, Langston AA, Perfect JR, et al. Cost effectiveness of posaconazole versus fluconazole for prevention of invasive fungal infections in US patients with graft-versus-host disease. Am J Health Syst Pharm 2012;69:149—56. [15] Michallet M, Gangneux JP, Lafuma A, Herbrecht R, Ribaud P, Caillot D, et al. Cost effectiveness of posaconazole in the prophylaxis of invasive fungal infections in acute leukaemia patients for the French healthcare system. J Med Econ 2011;14:28—35. [16] Antosz O, Peyton-Thomas B, Selby C, Bozeman A, Leary C, Devarakonda S, Mansour R, et al. Comparison of posaconazole versus voriconazole in the induction of acute myeloid leukemia: impact on cost, safety, and efficacy.[Abstracts] Biol Blood Marrow Transplant 2017;23:S18—391 [479—480].
Please cite this article in press as: Tang L, et al. Posaconazole vs. voriconazole in the prevention of invasive fungal diseases in patients with haematological malignancies: A retrospective study. Journal De Mycologie Médicale (2018), https://doi.org/10.1016/j.mycmed.2017.11.003
MYCMED-742; No. of Pages 5 Journal de Mycologie Médicale (2017) xxx, xxx—xxx
Available online at
ScienceDirect www.sciencedirect.com
ORIGINAL ARTICLE/ARTICLE ORIGINAL
Posaconazole vs. voriconazole in the prevention of invasive fungal diseases in patients with haematological malignancies: A retrospective study L. Tang a,b, X.-F. Yang a,b, M. Qiao a,b, L. Zhang a,b, X.-W. Tang a,b, H.-Y. Qiu a,b, D.-P. Wu a,b, A.-N. Sun a,b,* a b
Department of hematology, the First Affiliated Hospital of Soochow University, Suzhou, China Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
Received 12 September 2017; received in revised form 6 November 2017; accepted 13 November 2017
KEYWORDS Posaconazole; Voriconazole; IFDs
Summary Background. — Posaconazole is superior to fluconazole or itraconazole in preventing invasive fungal diseases (IFDs) in patients with haematological malignancies; however, there have been reports of the comparing posaconazole and voriconazole. Methods. — This single-centre, retrospective study in China enrolled AML, ALL and MDS patients, among others. Prophylaxis with posaconazole or voriconazole was administered for patients recovering from neutropenia or who had achieved complete remission. The primary emphasis was proven, probable, or possible IFDs during treatment. The cost-effectiveness, the proportion of adverse events and systemic antifungal treatment were the secondary emphasis. Results. — A total of 164 patients were recruited to receive posaconazole (n = 81) or voriconazole (n = 83). The incidence rates of proven, probable or possible IFD were 2.46% (2/81) and 4.82% (4/83) in the posaconazole group and voriconazole groups, respectively (P > 0.05). Only one patients experienced adverse events on posaconazole, while eleven patients experienced such events on voriconazole (P = 0.003). Patients receiving posaconazole or voriconazole had similar proportions of systemic antifungal treatment: 18.52% (15/81) in the posaconazole group and 16.87% (14/83) in the voriconazole group (P > 0.05). In the cost-effectiveness analysis, the prognosis of the two groups was close, but the drug acquisition costs of posaconazole were higher than those of voriconazole (P = 0.021).
* Corresponding author at: The First Affiliated Hospital of Soochow University, Jiang Su, China. E-mail address: [email protected] (A.N. Sun). https://doi.org/10.1016/j.mycmed.2017.11.003 1156-5233/# 2017 Published by Elsevier Masson SAS.
Please cite this article in press as: Tang L, et al. Posaconazole vs. voriconazole in the prevention of invasive fungal diseases in patients with haematological malignancies: A retrospective study. Journal De Mycologie Médicale (2018), https://doi.org/10.1016/j.mycmed.2017.11.003
+ Models
MYCMED-742; No. of Pages 5
2
L. Tang et al. Conclusion. — Posaconazole and voriconazole have the same prophylactic effect against IFDs in high-risk neutropenic Chinese patients. However, the safety of posaconazole is superior to that of voriconazole, while in terms of cost-effectiveness, voriconazole has an advantage over posaconazole. # 2017 Published by Elsevier Masson SAS.
Introduction Invasive fungal diseases (IFDs) are diseases in which fungi invade the body and reproduce in the tissues, organs or blood, ultimately causing inflammation and tissue injury [1]. The incidence of IFDs has steadily increased in recent years in patients with haematological malignancies, because of the development of chemotherapy regimes and transplantations. IFDs are an important threat to patients with haematological malignancies and are associated with significant morbidity and mortality. Patients who undergo induction chemotherapy and haematopoietic stem cell transplantation (HSCT) are at high risk of developing IFDs. There are no specific clinical manifestations during the early stage of IFDs, and the limited curative effect and adverse reactions of antifungal drugs have yet to be resolved. Therefore, prophylaxis against IFDs is particularly important. Posaconazole is a broad-spectrum oral triazole, and is effective as a prophylaxis in reducing IFDs in high-risk patients [2]. The aim of this study was to compare the efficacy, safety and cost-effectiveness of posaconazole and voriconazole in the prevention of IFDs in Chinese patients with haematological malignancies, who received chemotherapy or haematopoietic stem cell transplantation.
Patients and methods Patients Patients were collected from the first affiliated hospital of Soochow University from January 2016—April 2017 in either general wards or transplant purification warehouses with posaconazole or voriconazole treatment for preventing IFDs. All of the patients either had persistent neutropenia (absolute neutrophil count < 0.5 109/L) or were expected to develop neutropenia in 3—5 days. Patients received standard chemotherapy, intensive chemotherapy or HSCT. All patients received posaconazole oral suspension (40 mg/mL) 200 mg, 3 times/day, or voriconazole 200 mg, 2 times/day. Patients were excluded if they had an electrolyte imbalance, severe renal insufficiency, liver dysfunction, or serious unstable cardiovascular or central nervous system abnormality before using posaconazole or voriconazole. Patients using other antifungal drugs for preventing IFDs were also excluded from the study.
Efficacy evaluation All patients were monitored carefully for any evidence of IFDs at the beginning and the end of the prophylaxis. Comprehensive surveillance included high-resolution chest computed tomography, culture of associated tissues or
samples and Aspergillus galactomannan assay for patients developing any signs or symptoms of infection during the treatment phase. The primary emphasis was the incidence of proven, probable, or possible diagnosis of IFDs during treatment, according to the European Organization for the Research and Treatment of Cancer and the Mycoses Study Group. Proven or probable IFDs were defined as invasive fungal infection breakthrough [1]. We also recorded the drug acquisition costs of posaconazole and voriconazole during the prevention of IFDs. The cost-effectiveness, the proportion of adverse events and systemic antifungal treatment were the secondary emphases.
Safety evaluation All adverse events were recorded and assessed according to the Common Toxicity Criteria grading system of the National Cancer Institute [3]. Important adverse events were defined as those needing medical intervention to change the treatment protocol.
Statistical analysis Data are mainly presented as medians and (ranges) and counts and (percentages). Comparisons between categorical variables were performed by Fisher’s exact test or the Chi2 test; for continuous variables, Student’s t-test or analysis of variance was used. The survival distribution function was estimated using the Kaplan—Meier product-limit method. P < 0.05 indicated statistically significant differences.
Results Patients’ characteristics A total of 164 patients were recruited to receive either posaconazole (n = 81) or voriconazole (n = 83). The two groups had similar baseline characteristics in terms of demographic data, underlying diseases and neutropenia duration (Table 1).
IFDs breakthrough rates and systemic antifungal therapy During the treatment phase, the average days of drug administration were 19.49 days and 14.81 days in the posaconazole group and voriconazole groups, respectively (P > 0.05). There were no proven diagnoses in the groups, and each had one probable pulmonary fungal infection who died following Ambisome antifungal therapy. The breakthrough rates of
Please cite this article in press as: Tang L, et al. Posaconazole vs. voriconazole in the prevention of invasive fungal diseases in patients with haematological malignancies: A retrospective study. Journal De Mycologie Médicale (2018), https://doi.org/10.1016/j.mycmed.2017.11.003
+ Models
MYCMED-742; No. of Pages 5
Posaconazole vs. voriconazole in the prevention of invasive fungal diseases Table 1
3
Clinical characteristics of the patients. Posaconazole Voriconazole P (n = 81) (n = 83) value
Age, year Mean SD Median (range) Sex, n (%) Male Female Underlying diseases AML ALL MDS SAA HAL NHL MM Therapy methods Chemotherapy HSCT Total duration of neutropenia in treatment phase, days Median (range) Mean SD
35.28 1.83 32 (10 78)
37.19 1.58 0.180 37 (5 70)
47 (58.02%) 34 (41.98%)
47 (56.63%) 36 (43.37%)
0.317
29 (35.80%) 30 (37.04%) 11 (13.58%) 6 (7.41%) 0 2 (2.47%) 3 (3.70%)
53 (63.86%) 24 (28.92%) 2 (2.41%) 2 (2.41%) 2 (2.41%) 0 0
0.352
33 (40.74%) 48 (59.26%)
64 (77.11%) 19 (22.89%)
0.655
14 (0 51) 14.85 1.16
13 (0 44) 0.121 13.46 0.88
Figure 1 Kaplan—Meier analysis of overall survival between the posaconazole group and the voriconazole group (P = 0.688).
AML: acute myelogenous leukaemia; ALL: acute lymphoblastic leukaemia; MDS: myelodysplastic syndrome; SAA: severe aplastic anaemia; HAL: hybrid acute leukaemia; NHL: non-Hodgkin’s lymphoma; MM: multiple myeloma; SD: standard deviation; HSCT: haematopoietic stem cell transplantation.
IFDs were 1.23% (posaconazole) vs. 1.20% (voriconazole) (P > 0.05). There were 15 patients in the posaconazole group and 14 in the voriconazole group receiving amphotericin B or caspofungin as systemic antifungal therapy, after they developed symptoms of IFDs (P > 0.05).
Figure 2 Results of follow-up between the posaconazole group and the voriconazole group. A total of 10 people died in each group, with no obvious statistical significance.
Safety
collected (due to various reasons). These findings indicate that the costs of preventing IFDs in the posaconazole group were significantly higher than that in the voriconazole group.
Adverse events were comparable between groups. Twelve serious adverse events were reported. One patient (1.23%) had a gastrointestinal reaction in the posaconazole group; one case of akoasm (1.20%), two cases of visual hallucination (2.41%) and eight cases of liver dysfunction (9.64%) were noted in the voriconazole group. There were no instances of renal impairments or long QTc intervals, among other similar complication. The entirety of adverse events in the posaconazole group compared with the voriconazole group (1 vs. 11 patients, P = 0.003), indicated posaconazole was obviously safer than voriconazole in the prevention of IFDs.
Cost of antifungal prophylaxis During the treatment phase, the average consumption on drug acquisition costs were 16,169.63 760.36 (4980 29,880 RMB) in the posaconazole group, and 13,062.65 692.95 (3900 27,300 RMB) in the voriconazole group (P = 0.021). The costs of treating IFDs were not
Follow-up Followed-up extended to May 2017; 38 patients failed to follow-up. The overall survival rates of the two groups were not obviously different (Fig. 1). Twenty patients out of 126 died, with ten patients dead in each group. There were two cases (3.70%) of infection-related death in the posaconazole group and one case (1.92%) in the voriconazole group (P > 0.05) (Fig. 2). There were 15 cases of aGVHD in HSCT patients, a condition that can be controlled by anti-rejection treatments: 11/48 (22.92%) in the posaconazole group vs. 4/ 19 (21.05%) in the voriconazole group (P = 0.574).
Discussion In recent years, a number of clinical trials have shown that patients with haematological malignancies who used
Please cite this article in press as: Tang L, et al. Posaconazole vs. voriconazole in the prevention of invasive fungal diseases in patients with haematological malignancies: A retrospective study. Journal De Mycologie Médicale (2018), https://doi.org/10.1016/j.mycmed.2017.11.003
+ Models
MYCMED-742; No. of Pages 5
4
L. Tang et al.
posaconazole for preventing IFDs were more effectively treated than those using fluconazole or itraconazole [4—6], but there have been few studies comparing posaconazole and voriconazole. Posaconazole and voriconazole are both newgeneration triazole broad-spectrum antifungal drugs. Posaconazole interferes with fungal cytochrome P450 enzyme synthesis and then further inhibits fungal cell wall synthesis of ergosterol and has antimicrobial effects against Candida, Aspergillus species, Cryptococcus neoformans, and bacteria, such as sickle-shaped bacteria [7]. Voriconazole inhibitis ergosterol biosynthesis of the P450 element 14-alpha sterol to its methylated form, thus inhibiting ergosterol biosynthesis and playing antifungal activities against Candida, Aspergillus species, genera of sickle-shaped bacteria, Cryptococcus yeast, other bacteria and other pathogenic fungi, with broad-spectrum antimicrobial effects [8]. The IDSA recommends that during chemotherapy or transplantation in patients with haematological malignancies, posaconazole should be administered as a first-line antimicrobial for preventing IFDs, with voriconazole can be as a secondary treatment [9]. However, in recent years, after chemotherapy or transplantation, the incidence of Candida infections fell, while Aspergillus and other fungal infection rates rose [10]. Voriconazole has more obvious resistance to Aspergillus fungus activity: therefore, the usage of voriconazole in haematological malignancies after chemotherapy or transplantation for preventing IFDs in China has increased years by years. This study included people with haematological malignancies undergoing chemotherapy and haematopoietic stem cell transplantation. Posaconazole and voriconazole exhibited no obvious differences in terms of curative effect for preventing IFDs. However, in this study, the posaconazole group exhibited only one case of gastrointestinal reaction (1.23%), lower than in an international report [11], one case of akoasm (1.20%), two cases of visual hallucinations (2.41%) and eight cases of liver dysfunctions (9.64%) in the voriconazole group. However, because of the presence of fewer samples, the ratios are lower than previously reported [12]. Regarding adverse events, on the whole, posaconazole was associated with significantly fewer events than voriconazole; thus, safety was higher than that of voriconazole. In clinical setting, cost-effective analysis is the most common method of valuating economics by far, and the cost-effective ratio is the commonly used method (the average cost per unit effects need: smaller cost-effective ratios indicate more efficiency). Compared with fluconazole or itraconazole, posaconazole has good economic benefit [13,14], posaconazole to be more efficacious and less expensive than standard azole agents [15]. However, there are fewer reports comparing posaconazole and voriconazole. The prices of posaconazole at home and abroad are higher: therefore, the expense of using posaconazole in this study was obviously higher than the price of voriconazole, as indicated by Antosz et al. [16] are the same. In this study, the effects of the two groups in the prevention of IFDs were the same, and there was no obvious difference in systemic antifungal treatment, but the drug costs of the preventing IFDs with voriconazole are lower than the costs with posaconazole. Therefore, in the cost-effectiveness analysis, voriconazole is superior to posaconazole.
Conclusion Posaconazole and voriconazole have favourable clinical efficacy in the prevention of IFDs. However, during the voriconazole treatment period for the prevention of IFDs, the possibilities of visual impairment and other adverse events (such as abnormal liver function) still need to be considered. We should strengthen the detection of drug concentration and actively adjust the dosage of drugs to avoid adverse drug reactions. The appropriate antifungal agents were also selected according to the different strains of drug-resistant strains. Posaconazole has better safety and preferable tolerance for patients with chemotherapy or transplantation. However, the drug costs of posaconazole are higher than those of voriconazole; therefore, the costeffectiveness of voriconazole is superior to that of posaconazole. Therefore, we recommend that patients who are young and have good liver and kidney function use voriconazole for the prevention of IFDs and that patients who are older have more complications and more feasible infection factors use posaconazole for the prevention of IFDs. As the drug costs of posaconazole are still higher domestically, it is used less, and this study was only a single-centre study. Further, multicentre controlled studies are needed to expand the sample size.
Disclosure of interest The authors declare that they have no competing interest.
References [1] De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 2008;46:1813—21. [2] Cornely OA, Ullmann AJ. Numbers needed to treat with posaconazole prophylaxis to prevent invasive fungal infection and death. Clin Infect Dis 2008;46:1626—7. [3] Trotti A, Byhardt R, Stetz J, Gwede C, Corn B, Fu K, et al. Common toxicity criteria: version 2.0. An improved reference for grading the acute effects of cancer treatment: impact on radiotherapy. Int J Radiat Oncol Biol Phys 2000;47:13—47. [4] Döring M, Eikemeier M, Cabanillas Stanchi KM, Hartmann U, Ebinger M, Schwarze CP, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. New Eng J Med 2007;356:348—59. [5] Ullmann AJ, Lipton JH, Vesole DH, Chandrasekar P, Langston A, Tarantolo SR, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. New Eng J Med 2007;356:335—47. [6] Shen Y, Huang XJ, Wang JX, Jin J, Hu JD, Yu K, et al. Posaconazole vs. fluconazole as invasive fungal infection prophylaxis in China: a multicenter, randomized, open-label study. Int J Clin Pharmacol Ther 2013;51:738—45. [7] Aperis G, Alivanis P. Posaconazole: a new antifungal weapon. Rev Recent Clin Trials 2011;6:204—19. [8] Mitra A, Savant V, Aralikatti A, Dean S, Shah S. The use of voriconazole in the treatment of cylindrocarpon keratomycosis. Cornea 2009;28:217—22.
Please cite this article in press as: Tang L, et al. Posaconazole vs. voriconazole in the prevention of invasive fungal diseases in patients with haematological malignancies: A retrospective study. Journal De Mycologie Médicale (2018), https://doi.org/10.1016/j.mycmed.2017.11.003
+ Models
MYCMED-742; No. of Pages 5
Posaconazole vs. voriconazole in the prevention of invasive fungal diseases [9] Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenia patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2011;52:e56—93. [10] Neofytos D, Horn D, Anaissie E, Steinbach W, Olyaei A, Fishman J, et al. Epidemiology and outcome of invasive fun#infection in adult hematopoietic stem cell transplant recipients: analysis of multicenter Prospective Antifungal Therapy (PATH) Alliance registry. Clin Infect Dis 2009;48:265—73. [11] Raad II, Graybill JR, Bustamante AB, Cornely OA, Gaona-Flores V, Afif C, et al. Safety of long-term oral term oral posaconazole use in the treatment of refractory invasive fungal invasive fungal infections. Clin Infect Dis 2006;42:1726—34. [12] Hoffman HL, Rathbun RC. Review of the safety and efficacy of voriconazole. Expert Opin Investing Drugs 2002;11:409—29. [13] Jansen JP, O’Sullivan AK, Lugtenburg E, Span LF, Janssen JJ, Stam WB. Economic evaluation of posaconazole versus fluco-
5
nazole prophylaxis in patients with graft-versus-host disease (GVHD) in the Netherlands. Ann Hematol 2010;89:919—26. [14] O’Sullivan AK, Weinstein MC, Pandya A, Thompson D, Langston AA, Perfect JR, et al. Cost effectiveness of posaconazole versus fluconazole for prevention of invasive fungal infections in US patients with graft-versus-host disease. Am J Health Syst Pharm 2012;69:149—56. [15] Michallet M, Gangneux JP, Lafuma A, Herbrecht R, Ribaud P, Caillot D, et al. Cost effectiveness of posaconazole in the prophylaxis of invasive fungal infections in acute leukaemia patients for the French healthcare system. J Med Econ 2011;14:28—35. [16] Antosz O, Peyton-Thomas B, Selby C, Bozeman A, Leary C, Devarakonda S, Mansour R, et al. Comparison of posaconazole versus voriconazole in the induction of acute myeloid leukemia: impact on cost, safety, and efficacy.[Abstracts] Biol Blood Marrow Transplant 2017;23:S18—391 [479—480].
Please cite this article in press as: Tang L, et al. Posaconazole vs. voriconazole in the prevention of invasive fungal diseases in patients with haematological malignancies: A retrospective study. Journal De Mycologie Médicale (2018), https://doi.org/10.1016/j.mycmed.2017.11.003