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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

The current WHO goal of ending the global TB epidemic by 2035 will not be achieved without considerable new advances in TB treatment. A growing body of evidence has indicated that the current dose of rifampicin (10mg/kg) is inadequate. Several studies have suggested that dose escalation (to 20-35mg/kg) is safe and that higher doses (35mg/kg) may accelerate clearance of TB bacteria from the sputum of infected individuals. However, these studies have almost entirely been completed on HIV-negative TB patients, or TB-HIV-co-infected patients without severe immunosuppression who are not yet receiving antiretroviral therapy (ART). The challenge is to establish that a higher dose of rifampicin is safe for these patient groups.

As Uganda moves towards early initiation of ART, drug-drug interactions between rifampicin and efavirenz need to be assessed. It is also not clear if high dose rifampicin is safe in patients on efavirenz-based ART. Dr Sekaggya-Wiltshire proposed to determine the effect of higher doses of rifampicin (20mg/kg and 35mg/kg) on efavirenz concentrations and the safety of TB regimens containing high-dose rifampicin in TB-HIV-infected patients also receiving efavirenz-based ART.

She and her team are enrolling 160 TB-HIV-co-infected patients at the Infectious Diseases Institute for a randomised open-label phase IIb clinical trial. Patients diagnosed with TB will be randomised to one of three rifampicin doses of 10 (control), 20 or 35mg/kg for the first 8 weeks of TB treatment. Isoniazid, pyrazinamide and ethambutol will be given in their standard doses. Patients who are not on ART will be initiated on efavirenz-based ART after two weeks of TB treatment. Alanine transaminase will be done two weekly and sputum culture performed after 8 weeks of treatment.

The study aims to determine whether TB-HIV-co-infected patients on efavirenz-based ART and higher doses of rifampicin (20mg/kg and 35mg/kg) have lower concentrations of efavirenz, develop liver toxicity more frequently compared to patients on standard dose (10mg/kg). It will also determine the proportion of patients who remain sputum culture-positive after 8 weeks of treatment in each treatment arm.

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 results of this study will inform phase III clinical trials in a larger group of TB-HIV-co-infected patients to determine the utility of higher doses of rifampicin in this population. As regards capacity development, Dr Sekaggya-Wiltshire aims to enhance her capabilities in patient-oriented research and ability to perform pharmacokinetic-focused clinical trials and learn new model-based approaches for the analysis of pharmacokinetic data.

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