A clinical trial of dexamethasone to reduce mortality in cryptococcal meningitis

Cryptococcal meningitis is a brain infection due to a yeast called Cryptococcus neoformans. It is important because it is a major cause of death in people infected with HIV. There are over 600 000 deaths each year, and most of these occur in poorer countries in Africa and Asia. Even if patients receive treatment with antifungal drugs, the death rate remains high - about 55% of people with disease in Asia and 70% in Africa will die within 3 months of diagnosis. A combination of antifungal drugs is given to kill the yeast, but researchers have been unable to improve on the antifungal treatment combination that has been recommended for the past 10 years. This is despite extensive research. We believe that new approaches are needed to try and improve outcome in this disease. The features of infectious diseases are the result of not only the infectious agent, but also the way our bodies respond to them. When our bodies? immune systems fight infection, this causes inflammation which can sometimes make disease worse. When people have cryptococcal meningitis, there is inflammation and raised pressure in the brain. The inflammation can result in parts of the brain dying (a stroke). The raised pressure leads to the brain getting squeezed (compressed) against the inside of the skull. This can impair the blood supply and can directly damage the brain tissue itself. These processes can lead to death. Steroids are drugs that can reduce inflammation, and are frequently used to lower raised pressure in brain diseases. They have been found to be useful in other forms of meningitis, such as acute bacterial meningitis and tuberculous meningitis. These diseases share some features with cryptococcal meningitis. We want to test whether giving dexamethasone, a steroid, alongside antifungal therapy, can reduce the death rate in people with cryptococcal meningitis. Dexamethasone is cheap, safe, and widely available, and if successful is a treatment that would be affordable and practical for the majority of patients around the world with this disease. We want to do this study in Africa and Asia, because this is where most people with cryptococcal meningitis live.

Cryptococcal meningitis is the leading cause of death in HIV patients in Asia and Africa with death rates between 55 and 70%. There are an estimated 625 000 deaths each year, most occurring in poorer countries and within 3 months of diagnosis. There has been no major advance in treatment since 1997 - no combination of antifungal drugs with greater sterilizing power than amphotericin and flucytosine has since been identified. In order to make a significant impact on mortality, alternative approaches need to be trialled. Adjuvant therapies are relatively untested in cryptococcal meningitis. Raised intracranial pressure, vasculitis with infarction and cerebral oedema are all complications of cryptococcal meningitis and are believed to contribute towards its high mortality. These pathologies are potentially modifiable with dexamethasone. Dexamethasone is a corticosteroid which is frequently used to treat intracranial pathology including vasculitides, raised pressure, and cerebral oedema. It is of proven benefit in reducing the death rate of tuberculous meningitis, a chronic meningitis that has some pathophysiological similarities to cryptococcal meningitis. Moreover, it has an excellent safety profile, is cheap and practicable. In addition, animal studies show that dexamethasone does not impair the action of antifungal drugs.
Therefore, we propose a multicentre double blind randomised controlled trial of dexamethasone in HIV infected patients with cryptococcal meningitis. The study will be based in countries in Africa (Uganda, South Africa, Malawi) and Southeast Asia (Thailand, Laos, Vietnam, Indonesia) where this disease is a significant health burden, and in centres with track records of successful completion of large clinical trials and the subsequent translation of findings into national and international policy. The multi-centre nature of the trial, recruiting in African and Asian countries, ensures that the results of the trial will have generalizability and impact. The primary endpoint will be survival until 10 weeks after randomization. The study will have 80% power to detect a reduction in the death rate of 30% (Hazard Ratio 0.7), and will require 880 patients (allowing for 10% loss to follow up). The study will also have 80% power to detect a 40% reduction in death rate in each continent. Patients will receive optimised antifungal therapy and be randomised to receive dexamethasone or identical placebo. Secondary endpoints include disability, survival to 6 months, adverse event rates, opportunistic infection rates and the rate of fungal clearance.