Reply to Rajasingham and Boulware
Reply to Rajasingham and Boulware
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回复拉贾辛厄姆和布尔韦尔
DOI：
10.1093/cid/ciz040
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发表时间：
2019
影响因子：
11.8
通讯作者：
Jarvis J
中科院分区：
文献类型：
--
作者：
Jarvis J
2015年，《纽约时报》（New York Times）报道了图灵制药公司（Turing Pharmaceuticals）将乙胺嘧啶（Daraprim）的价格提高了500%后，引发了广泛的愤怒。乙胺嘧啶（Daraprim）是一种主要用于治疗晚期人类免疫缺陷病毒（HIV）疾病[1]患者的弓形虫病的药物。乙胺嘧啶并不是治疗受这种掠夺性定价影响的艾滋病毒相关机会性感染的唯一低成本仿制药；2016年，Merry和Boulware报告了氟胞嘧啶（5-FC）价格的爆炸式增长对美国治疗隐球菌脑膜炎的成本产生的巨大影响。氟胞嘧啶是一种60岁且易于制造的分子[3]，2周疗程的费用已上升至近30,000美元，比英国[3]的同等治疗费用高出9000%。因此，令人鼓舞的是，正如Rajasingham和Boulware在本期《临床传染病》杂志上所报道的那样，在美国食品和药物管理局（FDA）批准了3种新的非专利配方后，氟胞嘧啶的定价明显下降。尽管与乙胺嘧啶[6]一样，氟胞嘧啶在美国仍然很昂贵，但这显然是朝着正确方向迈出的一步，而且非常及时，因为新的临床试验证据清楚地表明，氟胞嘧啶作为hiv相关隐球菌脑膜炎[6]联合治疗的一个组成部分至关重要。在最近的非洲隐球菌治疗进展（ACTA）试验中，氟胞嘧啶作为两性霉素B的伴用药显著优于大剂量氟康唑，导致10周生存率提高（风险比0.62,95%可信区间[CI] 0.45-0.84）。虽然改善氟胞嘧啶对美国患者的定价是一个非常积极的发展，但隐球菌疾病的大部分负担存在于低收入和中等收入国家（LMICs）；主要是撒哈拉以南非洲地区。在非洲，隐球菌性脑膜炎估计每年造成135,900人死亡，约占所有艾滋病毒相关死亡的15%；尽管扩大了抗逆转录病毒治疗（ART）计划，但病例数量仍然很高[8,9]。长期抗逆转录病毒治疗中断、停止或失败的患者数量的增加抵消了首次出现晚期艾滋病毒疾病bbb的患者数量的下降，并且在许多情况下，大多数隐球菌性脑膜炎患者现在都经历了抗逆转录病毒治疗[8,10]。中低收入国家隐球菌脑膜炎死亡率高的一个主要原因是缺乏获得有效治疗的机会。许多患者接受氟康唑单药治疗，同时使用两性霉素B为基础的治疗，由于费用和在资源有限的卫生保健设施中管理每日静脉输注的困难以及药物相关毒性而受到限制。因此，ACTA试验表明，缩短的7天两性霉素B脱氧胆酸加氟胞嘧啶疗程，以及大剂量氟康唑加氟胞嘧啶全口服联合治疗均不低于常规的2周两性霉素B脱氧胆酸治疗[6]，这是一个重大进展，突出了氟胞嘧啶在低mic中使用的重要性[6]。在他们的文章中，Rajasingham和Boulware计算出，在美国对所有艾滋病患者普遍实施隐球菌抗原（CrAg）筛查，对那些检测到隐球菌抗原血症的人进行先发制人的治疗，以预防暴发性脑膜炎，可能会导致相当大的成本节约100。的峭壁
To the Editor—In 2015 there was widespread outrage after the New York Times publicized the 5000% increase in the price of pyrimethamine (Daraprim) by Turing Pharmaceuticals, a drug used primarily to treat toxoplasmosis in patients with advanced human immunodeficiency virus (HIV) disease [1]. Pyrimethamine was not the only previously low-cost generic medication for an HIV-related opportunistic infection subject to such predatory pricing; in 2016 Merry and Boulware reported the dramatic impact a similarly explosive increase in the price of flucytosine (5-FC) was having on the cost of treating cryptococcal meningitis in the United States [2]. The cost of a 2-week course of flucytosine, a 60 year-old and easy to manufacture molecule [3], had risen to nearly $30,000, 9000% higher than the equivalent treatment in the United Kingdom [2]. It is therefore encouraging to see the marked decline in flucytosine pricing in the United States following the Food and Drug Administration’s (FDA) approval of 3 new generic formulations, as reported by Rajasingham and Boulware in this issue of Clinical Infectious Diseases [4]. Although, as with pyrimethamine [5], flucytosine remains expensive in the United States, this is clearly a step in the right direction, and very timely, given new clinical trial evidence clearly showing the critical importance of flucytosine as a component of combination treatment for HIV-associated cryptococcal meningitis [6]. In the recent Advancing Cryptococcal Treatment for Africa (ACTA) trial, flucytosine was significantly superior to high-dose fluconazole as the partner drug for amphotericin B, leading to improved survival at 10 weeks (hazard ratio 0.62, 95% confidence interval [CI] 0.45–0.84)[6].Although improved flucytosine pricing for US patients is a very positive development, the bulk of the burden of cryptococcal disease lies in low-and middle-income countries (LMICs); primarily sub-Saharan Africa [7]. Cryptococcal meningitis causes an estimated 135,900 deaths annually in Africa [7], approximately 15% of all HIV-related deaths; the number of cases remains high despite the expansion of antiretroviral treatment (ART) programs [8, 9]. Increasing numbers of patients on long-term ART interrupting, stopping, or failing therapy are offsetting any decline in the numbers of patients presenting for the first time with advanced HIV-disease [8], and in many settings the majority of cryptococcal meningitis patients are now ART-experienced [8, 10]. A major contributor to the high death rates due to cryptococcal meningitis in LMICs is lack of access to effective treatments. Many patients are treated with fluconazole monotherapy, with use of amphotericin B based therapies limited by cost and the difficulties of managing daily intravenous infusions and drug-related toxicities in resource-constrained healthcare facilities. It was thus a major advance when the ACTA trial demonstrated that both an abbreviated 7-day course of amphotericin B deoxycholate plus flucytosine, and an all-oral combination of high dose fluconazole plus flucytosine were noninferior to conventional 2-week amphotericin B deoxycholate-based treatments [6], highlighting the importance of flucytosine access in LMICs [11]. In their article, Rajasingham and Boulware calculate that universal implementation of cryptococcal antigen (CrAg) screening for all individuals with AIDS in the United States, with preemptive treatment for those who have detectable cryptococcal antigenemia to prevent fulminant meningitis, could lead to considerable cost savings [4]. The CrAg