We are an International Multi-Organizational Coalition addressing gaps in the prevention, prompt diagnosis and management of AIDS globally.
Background and study aims
Over the last 10 years, many more people living with HIV in Africa have been able to start antiretroviral treatment (ART). However, about one-third of people living with HIV only seek care when they have advanced HIV disease (when their CD4 count falls below 200 cells/µl). The frequency of infections such as cryptococcal meningitis in this group is high. Cryptococcal meningitis, caused by a fungus, is the commonest form of meningitis in sub-Saharan Africa, resulting in about 180,000 deaths per year globally with over 75% of these occurring in sub-Saharan Africa.
Over half of the patients diagnosed with cryptococcal meningitis die within 10 weeks in sub-Saharan Africa, a death rate similar to Ebola virus disease. Fortunately, cryptococcal disease can be diagnosed earlier, before the development of life-threatening meningitis, using a simple blood test to detect a part of the fungal cell called cryptococcal antigen (CrAg). Studies have shown that 70% of people testing positive for CrAg in blood would progress to develop meningitis or die without a diagnosis if they are not given antifungal treatment. Routine screening for CrAg among people presenting to HIV centres, combined with oral antifungal (fluconazole) treatment for those who screen CrAg-positive, can therefore decrease the risk of cryptococcal meningitis and death. CrAg screening has now been recommended in the national HIV guidelines of 28 countries and screening programmes are being rolled out across sub-Saharan Africa.
However, there is now also evidence showing that CrAg-positive patients who are treated with fluconazole alone have a 2.5 to 3 times higher chance of dying compared to people with similar CD4 counts who test CrAg-negative, despite receiving this antifungal treatment. Up to 40% of people testing blood CrAg-positive may have asymptomatic (subclinical) cryptococcal meningitis diagnosed at the time of the screening test; these people need a combination of antifungal medicines to treat meningitis. Yet many patients decline the procedure to diagnose meningitis (lumbar puncture) and are thus not treated appropriately for meningitis.
Recent studies have shown that combined oral treatment of fluconazole plus flucytosine for 2 weeks is safe, has few unwanted side effects and works as well as the standard of 2 weeks of intravenous amphotericin B plus flucytosine for people treated in hospital with symptomatic cryptococcal meningitis. This study aims to compare how well this oral combination of fluconazole plus flucytosine works compared to fluconazole alone (the current recommended treatment) in reducing 6-month mortality in asymptomatic people with advanced HIV disease and a CrAg-positive blood test in Tanzania, South Africa and Vietnam.
