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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

Kanamycin is a commonly used component of combination treatments for multidrug-resistant TB. Unfortunately, in a significant number of patients, kanamycin use is associated with damage to the auditory system and loss of hearing.

There is some evidence that N-acetylcysteine protects against kanamycin-induced hearing loss. However, there are limited data on its use in Africa and in people infected with HIV as well as TB.

Dr Stella Mpagama has wide-ranging interests in the treatment of TB and other emerging and re-emerging infections. Based at the Kibong’oto Infectious Diseases Hospital, she has a strong interest in meeting both clinical and practical programmatic challenges in the treatment of infections, and in the interactions between health conditions. Few patients experience infection in the absence of other conditions; HIV–TB co-infections are common, but many patients have a combination of infections and non-communicable conditions. Dr Mpagama has been part of the EDCTP-funded PanACEA Consortium, which has been evaluating alternative treatment regimens for TB. Dr Mpagama has also carried out research on the first cohort of multidrug-resistant TB patients treated in Tanzania.

In her EDCTP Senior Fellowship, Dr Mpagama is addressing a significant issue associated with treatment of multidrug-resistant TB. As many as half of all patients may experience kanamycin-induced hearing loss, potentially affecting their quality of life and economic wellbeing. Focusing on patients with HIV–TB co-infections, Dr Mpagama is carrying out a randomised controlled phase IIb trial to determine the safety and efficacy of N-acetylcysteine to prevent damage to the auditory system.

Embedded in this project are a range of studies that will support the development of PhD and master’s students. Early-career researchers will have opportunities to monitor patient responses to treatment using the bacterial load assay, to use molecular assays to assess susceptibility to second-line drugs, and to carry out whole genome sequencing of isolates showing signs of drug resistance but with no detectable resistance mutations.

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 Mpagama’s Senior Fellowship project will answer an important question in the management of patients with multidrug-resistant TB, and could ensure that significant numbers of patients are spared serious hearing loss. In addition, it will create sufficient critical mass of researchers to establish a functional clinical trial unit locally.

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