A phase III randomised controlled trial of oral fluconazole plus flucytosine versus amphotericin B-based therapy for o

隐球菌性脑膜炎是艾滋病患者最常见的死亡原因之一，仅在非洲每年就与多达50万人的死亡有关。很大一部分患者死于感染，部分原因是目前推荐的治疗方法--两性霉素B，为期两周--在发展中国家的医院很难给予，因为它相对昂贵，需要静脉注射，而且有副作用，通常从第二周开始，这意味着需要通过频繁的血液测试进行监测。另一种口服片剂，氟康唑，是可用的，廉价的，目前常用的，效果要差得多。因此，基于研究小组早期的一些小规模试验，我们希望测试两种新的治疗方法，(1)短时间，1周的两性霉素B，和(2)使用大剂量氟康唑和另一种名为氟胞嘧啶的药物的联合治疗，它们与两性霉素B的2周一样快速有效地杀死静脉感染。我们将在一项更大的随机试验中将这些新疗法与2周的两性霉素B进行比较，以使我们能够看到它们在防止感染死亡方面是否同样有效。在研究治疗2周后，所有患者都将接受通常的氟康唑后续治疗，并将按照目前的建议开始使用治疗潜在艾滋病毒感染的药物，并随访10周。将对570名患者(每种替代治疗190名)进行研究。这是可靠比较治疗结果所需的最低数量。该项目是与马拉维和赞比亚三个中心的医生共同开发的，马拉维和赞比亚的病例较多，迫切需要替代的、负担得起的和实用的治疗方法。每个中心都有所需的实验室和进行此类试验的经验。已经证明，这两种试验疗法都比单独使用氟康唑见效快得多，副作用更少，在发展中国家比两周两性霉素B更容易给药。然而，如果两周两性霉素B被发现是最好的治疗方法，那么使用它所需的费用是合理的。将对这些治疗的成本和有效性进行比较，以帮助决定未来推荐哪种治疗。

Cryptococcal meningitis is one of the commonest causes of death in patients with AIDS andis associated with up to 500,000 deaths each year in Africa alone. A large proportion ofpatients die from the infection, in part because the current recommended treatment,amphotericin B for 2 weeks, is difficult to give in hospitals in the developing world, becauseit is relatively expensive and needs to be given intravenously and has side effects, oftenstarting in the second week, meaning monitoring is needed with frequent blood tests. Thealternative oral tablet treatment, fluconazole, that is available and cheap and currentlycommonly used, is much less effective.Therefore, based on a number of earlier small trials by the study team, we wish to test 2new treatments, (1) Short, 1-week amphotericin B, and (2) Combination tablet treatmentwith high dose fluconazole plus another drug called flucytosine, that are as fast and effectivein killing the infection as 2 weeks of amphotericin B. We will compare these new treatmentswith 2 weeks amphotericin B, in a larger, randomised trial that will enable us to see whetherthey are as good in preventing deaths from the infection. After 2 weeks of the studytreatments, all patients will receive the usual follow on therapy with fluconazole, and will bestarted on drugs for the underlying HIV infection, as currently recommended, and followedup for 10 weeks. 570 patients (190 given each alternative treatment) will be studied. This isthe minimum number needed to reliably compare the results of the treatments.The project has been developed with doctors in 3 centres in Malawi and Zambia where thereare many cases and where alternative, affordable and practical treatments are urgentlyneeded. Each centre has the laboratories needed, and experience in doing such trials. Bothtest treatments have been shown to be much more rapidly effective than fluconazole alone,and would have less side effects and be much more easily given in developing countries than2 weeks amphotericin B. However, if 2 weeks amphotericin B was found to be the besttreatment, then the costs required for its use could be justified. The costs as well as theeffectiveness of the treatments will be compared to help decide which treatment torecommend in the future.