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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

Parasitic worm infections such as onchocerciasis (the cause of river blindness) and lymphatic filariasis (responsible for elephantiasis) affect some 200 million people and have major health, social and economic impacts.

The availability of safe and effective treatments and use of mass drug administration programmes have led to great progress in disease control and the prospect of disease elimination. However, current drug treatments have drawbacks: they do not kill adult worms effectively, which can continue to produce microfilariae that can be transmitted to others, and they cannot be used in areas where people may also be infected with another parasitic worm, Loa loa, since death of L. loa parasites can trigger a potentially deadly inflammatory response in the brain.

In his Senior Fellowship, Dr Alexander Debrah is testing a new mass drug administration that overcomes these challenges and could provide an alternative or complementary strategy for disease elimination.

His project takes advantage of the fact that the parasitic worms responsible for onchocerciasis and lymphatic filariasis are dependent on a commensal bacterium known as Wolbachia, but L. loa is not. Laboratory studies have shown that existing drugs can kill Wolbachia. These include doxycycline, although it is relatively slow-acting, and rifampicin, a mainstay of TB treatment.

In practice, however, rifampicin is less potent than laboratory studies suggest, because of the way that the drug is metabolised in the body. This has encouraged testing of high-dose rifampicin, which has been found to be safe in TB trials. Furthermore, pre-clinical studies have revealed a synergistic interaction between rifampicin and albendazole, one of the drugs currently used in mass drug administration programmes, so shorter treatment regimes could be possible.

The core of Dr Debrah’s project will be two phase II trials comparing the efficacy of high-dose rifampicin and albendazole (for 7 days or 14 days) and 28 days of doxycycline or ivermectin (another commonly used drug in mass drug administration programmes). One trial will focus on onchocerciasis and the second on lymphatic filariasis.

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 Debrah’s research will provide important data on an innovative new approach for control of parasitic worm infections, based on currently available drug treatments. It would have the potential to provide an alternative strategy for mass drug administration, particularly important for the 20% of geographic areas where the presence of Loa loa restricts use of existing drugs and for locations where resistance to existing treatments is beginning to emerge.

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