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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 resistance is a growing problem in TB. In 2018, there were around half a million new cases of drug-resistant TB globally and an estimated 214,000 deaths. South Africa, particularly KwaZulu Natal, is badly affected by drug-resistant TB and has experienced the largest outbreak of extremely drug-resistant (XDR) TB ever reported.

Identification of drug resistance is important to ensure that patients are started on effective drugs as rapidly as possible and are spared the side effects of powerful drugs from which they will derive no benefit. However, culture methods to determine resistance take many weeks, while quicker molecular tests screen for only a few specific resistance genes.

Professor Nesri Padayatchi has contributed to multiple areas of TB research, and was the recipient of the South African Medical Research Council’s Silver Scientific Merit Award. She also has extensive practical experience of care for patients with MDR- and XDR-TB. In her Senior Fellowship, Professor Padayatchi is exploring the potential of whole genome sequencing to provide a comprehensive picture of resistance genes to inform treatment of MDR-TB and XDR-TB.

The mechanisms of drug resistance in Mycobacterium tuberculosis (Mtb) are complex, and mutations in many genes may contribute to reduced drug susceptibility. Whole genome sequencing is becoming more widely available and has the advantage of providing information relatively quickly across the entire Mtb genome. Recent studies have shown that there is a good correlation between resistance predicted on the basis of genetic information and that observed in tests with cultured bacteria.  

In her Senior Fellowship project, Professor Padayatchi is undertaking a trial comparing use of whole genome sequencing with conventional methods for detecting resistance. The trial will focus on patients first screened with the Xpert MTB/RIF diagnostic so are known to have drug-resistant TB, and aims to recruit patients with both MDR-TB and XDR-TB. On the basis of genome data, experts will select treatments likely to be most effective in each patient.

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.

Inadequate treatment of MDR-TB delays recovery, exposes patients to drugs with the potential to cause a range of significant side effects, and increases the risk that more extensive drug resistance develops. Whole genome sequencing is emerging as a tool that could overcome many of these challenges. Professor Padayatchi’s study will provide important evidence on the clinical benefits of its use in an area with one of the world’s heaviest burdens of MDR-TB and XDR-TB.

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