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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

More than half a million new cases of multidrug-resistant (MDR) TB occurred in 2017 and an estimated 240,000 people died of MDR-TB. Of these cases, around 6% had extremely drug-resistant TB (XDR-TB) which is difficult to diagnose, hard to treat, and has a very high mortality rate. In addition, failure to identify and treat MDR-TB cases promotes the spread of infection in communities.

Control of TB will ultimately depend on a good understanding of the origins and spread of MDR-TB and XDR-TB. However, despite the major TB burden in sub-Saharan Africa in general and South Africa in particular, there is limited understanding of Mtb evolution.

In her Senior Fellowship, Dr Elizabeth Streicher is using whole genome sequencing of MDR-TB and XDR-TB isolates to develop a better understanding of drug-resistant strains, how they have spread, and factors affecting their survival.

Dr Streicher has a long-standing interest in the use of genetic approaches to characterise Mtb strains, having been the first researcher in Africa to introduce a rapid genotyping tool, spoligotyping, and using that and other approaches to investigate the spread of resistant strains. She has also established a valuable biobank of more than 45,000 Mtb samples.

Conventionally, it is assumed that resistance mutations reduce the fitness of bacterial strains, hindering their ability to spread. However, molecular studies have shown that certain MDR-TB and XDR-TB strains have managed to establish themselves, and seeded new outbreaks following migration of infected patients, suggesting that they can compete effectively with non-resistant strains.

Concentrating on the Western Cape Province, which has a very high burden of XDR-TB, Dr Streicher is using whole-genome sequencing to provide a higher resolution view of the genetic make-up drug-resistant Mtb.  She plans to map the full range of resistance-associated mutations in different outbreaks, and to determine how changes in diagnostic approaches and recommended treatment regiments affected the spread of different strains. She also plans to assess the extent of drug-resistant TB in other southern African countries.

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.

Dr Streicher’s Senior Fellowship will improve understanding of the mechanisms driving the emergence and spread of XDR-TB in populations badly affected by both TB and HIV. It will generate important insights to inform control of highly problematic drug-resistant infections having a major impact on individuals and communities.

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