High Dose AMBISOME on a Fluconazole Backbone for Cryptococcal Meningitis Induction Therapy in sub-Saharan Africa: A Randomized Controlled Trial

隐球菌脑膜炎是非洲艾滋病毒感染者死亡的主要原因。目前推荐的治疗方法是一种名为阿替西霉素B脱氧胆酸盐的药物。用阿替霉素B治疗需要在医院进行14天的静脉输注，这使得给药变得困难和昂贵。它也会引起许多副作用，包括肾衰竭和低血细胞计数，因此必须进行密切的实验室监测。与长期住院有关的费用、管理方面的困难和对实验室监测的需要相结合，使得非洲大部分地区很难进行阿替霉素B治疗。目前唯一可用的替代疗法是氟康唑。用氟康唑治疗是不充分的，并且与大约60%的死亡率相关。一种修饰形式的阿替霉素B是可用的，称为脂质体阿替霉素B（Ambisome）。这是相当少的毒性比标准阿替霉素B，并被认为是有效的治疗隐球菌脑膜炎。它的使用受到治疗费用高的限制，但最近的数据表明，Ambisome疗程短得多，可能对隐球菌脑膜炎的治疗有效。由于其较低的毒性，可以安全地给予较高剂量的Ambisome，并且它在组织中也可以持续很长时间，从而提高了用很少（1，2或3）剂量提供高效诱导治疗的可能性。大量减少剂量和住院时间，以及降低Ambisome的价格，可能导致隐球菌脑膜炎的治疗成本不超过2周的常规阿替霉素B，并提供一种方便、安全和有效的替代常规阿替霉素B治疗。本研究旨在确定Ambisome治疗隐球菌性脑膜炎的最有效和最具成本效益的方案。目前正在进行的一项研究正在测试与标准14天疗程相比，一剂、两剂或三剂Ambisome治疗方案的安全性和对隐球菌感染清除率的影响。在这项拟议的大型临床试验中，将使用这些Ambisome方案中安全有效的最短方案，以确定其在预防隐球菌脑膜炎死亡方面是否与标准的14天阿替霉素B脱氧胆酸盐治疗一样有效。如果短程Ambisome治疗方案在治疗HIV相关隐球菌脑膜炎方面具有可比的有效性，则本研究的结果将导致国际治疗指南的变化，并为HIV相关隐球菌脑膜炎提供有效和实用的治疗选择，有可能防止数千人死亡。

Cryptococcal meningitis is a leading cause of death in HIV-infected individuals in Africa. The current recommended treatment is a drug called amphotericin B deoxycholate. Treatment with amphotericin B requires 14 days of intravenous infusions given in hospital, making it difficult and costly to administer. It also causes many side effects, including kidney failure and low blood count, making close laboratory monitoring essential. The combination of the costs associated with prolonged hospital admissions, the difficulties in administration and the need for laboratory monitoring make amphotericin B treatment difficult in much of Africa. The only alternative currently available treatment is called fluconazole. Treatment with fluconazole is inadequate, and is associated with death rates of approximately 60%.A modified form of amphotericin B is available called liposomal amphotericin B (Ambisome). This is considerably less toxic than standard amphotericin B, and is known to be efficacious in treatment of cryptococcal meningitis. Its use has been limited by the high cost of therapy, but recent data suggest that much shorter courses of Ambisome may be effective in the treatment of cryptococcal meningitis. Due to its lower toxicity, higher doses of Ambisome can be given safely, and it also persists for a long time in the tissues, raising the possibility of delivering highly effective induction therapy with very few (1, 2, or 3) doses. A large reduction in the number of doses and duration of hospitalisation, together with reduced pricing of Ambisome, may result in cryptococcal meningitis treatment costs that are not more than those with 2 weeks of conventional amphotericin B, and provide a convenient, safe and efficacious alternative to conventional amphotericin B therapy. This study aims to define the most effective and most cost-effective schedules for Ambisome use in the treatment of cryptococcal meningitis. A currently ongoing study is testing the safety and effect on rate of clearance of cryptococcal infection of one, two or three dose Ambisome treatment regimens compared to the standard 14-day course. The shortest of these Ambisome regimens that is found to be safe and effective will be utilized in this proposed large clinical trial to determine whether or not it is as effective as the standard 14-day amphotericin B deoxycholate treatment in terms of preventing deaths from cryptococcal meningitis. If short-course Ambisome treatment regimens were shown to be of comparable effectiveness in the treatment of HIV-associated cryptococcal meningitis, the results of this study would lead to changes in international treatment guidelines, and provide an effective and practical treatment option for HIV-associated cryptococcal meningitis with the potential to prevent many thousands of deaths.