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

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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.