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test the safety and efficacy of this new formulation in young children

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Bringing antiretroviral drugs to children

The CHAPAS trials have ensured that many more children with HIV have benefited
from life-saving antiretrovirals.

The challenge

The epidemiology of invasive fungal diseases has been evolving for the past two decades. In Uganda, HIV/AIDS has highlighted cryptococcal meningitis as a leading invasive fungal disease caused by Cryptococcus neoformans. Associated mortality is high, as 10-week survival rates in routine care are less than 50% after cryptococcal meningitis. Furthermore, the incidence of the common opportunistic fungi causing invasive disease in other immunosuppressive conditions such as cancer is not known.

Dr Achan aims in this study to determine the molecular epidemiology of Cryptococcus species causing cryptococcal meningitis and to describe the epidemiology of Candida, Cryptococcus and Aspergillus species that cause fungaemia in immunosuppressed individuals in Uganda. Additionally, the epidemiology of Madurella mycetomatis, which causes eumycetoma, will be described.

To characterise the epidemiology of invasive fungal diseases in Uganda, fungal isolates retrieved from blood culture will initially be identified to species level using the standard algorithm for identification. Identification methods will include India Ink stain, germ tube test, 10% potassium hydroxide mount, lactofuchsin stain, culture on Chrom-Candida, Niger birdseed, l-Canavanine glycine bromothymol blue agar, and use of biochemical tests such as API 20C. Antifungal susceptibility testing will be performed using the EUCAST method for yeasts and moulds. To describe the molecular ecology, polymerase chain reaction will be used to identify Cryptococcus species isolates from the patient’s cerebrospinal fluid and environment. Environmental samples will include birds’ guano, tree barks, soil and inanimate objects in the vicinity of the patient. Mycetoma granules from patients who present with the triad features of mycetoma will be assessed by direct microscopy using 10 % potassium hydroxide, culture on Saboraud dextrose agar while the tissue biopsy will be examined using histological stains like Haematoxylin and Eosin, Periodic Acid Schiff and Grocott Methamine Silver stains.

The project

The later CHAPAS-3 trial compared the efficacy and safety of three fixed-dose combinations including two without stavudine (found to have some long-term side effects in adults, leading to a recommendation that its use be discontinued in children). The trial the first of its kind in Africa studied nearly 500 children at four sites in two African countries.

Findings from this study will provide important baseline information on the epidemiological trend of invasive fungal diseases in Uganda for patient management and research.

ratios forfixed-dose combinations and on appropriatedosage according to weight. 

The CHAPAS-3 trial confirmed the effectiveness of fixed-dose combinations, providing further impetus to the rollout of antiretrovirals to children. Its evidence on abacavir informed the WHO recommendation of abacavir-containing combinations for first-line therapy in children. Trial data have also been used to support applications for regulatory approval for new scored efavirenz tablets.

Impact