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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 microbiota or microbiome, complex communities of microbes in mammals, play an important role in health and disease including for the induction and functioning of the immune system. However, baseline information on their composition and potential role(s) in pulmonary tuberculosis (TB) in sub-Saharan Africa, is lacking.

The overall purpose of Dr Kateete’s study is to determine the microbiome composition in patients with pulmonary tuberculosis and examine its relationship with treatment and immune response in these patients relative to their household healthy contacts without TB-infection and HIV-infection.

Specific aims of the study are, first, to examine the relationship between sputum and gut microbiome diversity and disease and the relationship between sputum and gut microbiome composition and treatment response among patients on first-line TB therapy, including whether dysbiosis resolves in patients who get cured of TB after successfully completing anti-TB therapy. Secondly, Dr Kateete will investigate the relationship between sputum and gut microbiome composition and inflammatory cytokine production capacity.

He will conduct a longitudinal study nested in a project at the Mulago National Referral Hospital in Kampala, Uganda, which maintains a cohort of 320 Xpert-positive, treatment-naïve adult TB patients with follow-up at months 2, 5, 12, 18 and 24. Sputum, stool and blood samples from 160 participants (purposive sampling) at baseline (day 0) and months 2, 5, 12, 18 & 24 for microbial and cytokine profiles. Out of the 160 participants, 100 will be pulmonary TB cases randomly selected from the parent MTI-cohort of whom 50 will be HIV-positive (TB+/HIV+) and 50 HIV-negative (TB+/HIV-). Sixty (60) household contacts will be similarly investigated as the comparator group (controls). Household contacts will be TB-negative family members of the 100 TB cases, of whom one half (30) will be HIV-positive without respiratory/pulmonary symptoms based on interferon-γ release assay (i.e. HIV+/TB- sub-group) while the other half (30) will be both HIV-negative and TB-negative i.e. the healthy contacts (HIV-/TB-).

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.

The study will deliver human microbiota profiles in tuberculosis from a TB-endemic/HIV-burden setting. Such results could be used as a reference for other settings in sub-Saharan Africa. The data also may reveal potential markers of TB-treatment response or failure. Such information is vital in devising novel region- or country-specific interventions.

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