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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

Despite being curable, tuberculosis (TB) remains the single biggest infectious cause of death globally and, in South Africa, kills more people than any other condition. Many cases of TB are never diagnosed and, despite good adherence to treatment, a significant proportion of cases encounter unfavourable treatment outcomens, in some settings as high as ~20%.

Therefore, there is not only a need for TB diagnostics but also for novel methods of prognosticating patients likely to have unfavourable outcomes. The microbiome (the collection of microbial genetic material within a specific environment) is an emerging research area as the microbiome has been implicated in disorders ranging from obesity to cystic fibrosis to survival in HIV-positive pneumonia patients. However, there are very little data in the context of tuberculosis. Moreover, the capacity in Africa to study the intersection of TB and the microbiome is also limited.

Dr Naidoo participates in an international multidisciplinary team comprised of a young TB researcher with emerging experience in computational biology (the fellow), mycobacteriologists and diagnosticians, pulmonologists with experience in the microbiome and lung disease, and immunologists.

In the MOSAIC study (Microbiome of South African Incident TB Cases), we propose to characterise the gut microbiome in 100 Xpert MTB/RIF-positive, culture-positive cases (pre-treatment, 2- and 6-months into treatment, and 6-, 12- and 18-months post-treatment), 50 matched symptomatic controls (Xpert-negative, culture-negative), and 200 healthy household contacts (two per case; culture-negative) in Cape Town, South Africa. We will leverage the SAMRC-funded project (BAR-TB) recruiting patients with presumptive TB, performing testing (Xpert, culture), microbiological and clinical follow-up. In MOSAIC, the team will, in addition to the work in BAR-TB, collect microbiome specimens, recruit and collect the same specimens from healthy contacts.

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 is expected to result in advances regarding the role of the microbiome in TB. In the long term, this may lead to targeting the microbiome for diagnosis or treatment outcome. The fellowship will develop the scientific, management and mentorship skills of the fellow, supports trainees and will enhance local computational biology capacity. Moreover, the study will collect additional specimens for future microbiome 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