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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

Drug-resistant tuberculosis (TB) remains a world-wide crisis. Despite early work indicating that drug-resistant Mycobacterium tuberculosis is less fit than its drug-susceptible counterparts, M. tuberculosis resistant to increasing numbers of drugs continues to emerge and spread. It has been shown that compensatory mutations exist that may explain the ability of the resistant bacilli to retain fitness. The challenge is to understand this mechanism.

Mutations in the inhA promoter are well known to cause resistance to at least two drugs. These mutations have been suggested to be a gateway to extensively drug-resistant TB (resistant to at least 4 key drugs). Dr Klopper proposes that, in addition to causing resistance, inhA promoter mutations act as compensatory mechanisms, overcoming negative effects of drug-resistance.

She will test this hypothesis by targeted mutagenesis and fitness assays. In particular, inhA promoter mutations cause the upregulation of two genes involved in mycolic acid synthesis (mabA and inhA), as well as one gene involved in haem biosynthesis (hemZ). Dr Klopper aims to show that this upregulation causes an increase in the number of mycolic acids synthesised, which in turn increases the functionality of mycolic acids. She will show that this function is to facilitate the sequestration of ferrous iron, nitric oxide or oxygen by isolation of mycolic acids and measurement of the concentration of these molecules in a solution containing mycolic acids.

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 focuses on an important drug-resistance mechanism and will aid in elucidating additional functions of this mechanism. This will contribute to a better understanding of the physiology of the bacillus and may lead to novel insights for drug design.

The fellowship will not only allow Dr Klopper to conduct this study plan but also plan longer-term projects emanating from its results, including the investigation of further structure-function relationships of different mycolic acids, as well as the related role of haem in the utilisation of reactive oxygen or -nitrogen species. Building out the project will increase opportunities for postgraduate student supervision, as well as international collaborations and publications.

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