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The DATURA trial is evaluating whether an intensified treatment regimen can reduce the disturbingly high risk of death from TB in people living with HIV.

Intensified TB treatment for people living with HIV 

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Although care for people living with HIV has improved markedly in recent years, around a quarter only start treatment when their CD4 white blood cell numbers have been severely depleted. This places them at greatly increased risk of other infections, including TB. As many as 30% of people living with HIV succumb to TB, accounting for 19% of global TB mortality.

HIV infections increase the risk of active TB disease, and also lead to reduced concentrations of TB drugs in the bloodstream, owing to abnormalities in the adsorption of TB drugs. Antiretroviral therapy can also interfere with the action of TB drugs. Conversely, antiretroviral therapy can also trigger a potentially deadly exaggerated immune response to TB (immune reconstitution inflammatory syndrome, IRIS).

The challenge

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The DATURA trial is evaluating an intensified TB treatment regimen designed to address these challenges in people living with HIV and with low CD4 cell counts.

Recent trials have confirmed the safety of high doses of the key TB drug rifampicin. The DATURA trial is combining high-dose rifampicin with a higher than usual dose of isoniazid. The trial team will liaise with the EDCTP-funded INTENSE TBM project, which is using high-dose rifampicin to reduce mortality associated with tuberculosis meningitis.

The trial regimen will also incorporate a corticosteroid (prednisone), shown in the EDCTP-funded PREDART trial to reduce the risk of IRIS reactions in patients starting antiretroviral treatment.

The trial will compare the intensified approach – 8 weeks of high-dose anti-TB drugs followed by 16 weeks of classical treatment, plus 6 weeks of prednisone – with the standard 24-week TB treatment regime. The trial will include nearly 1,000 patients from all four regions of sub-Saharan Africa, generating definitive evidence on the efficacy and safety of this new approach.

The project

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The DATURA trial is addressing a critical health issue in sub-Saharan Africa. If intensified treatment is shown to be more effective, it would have the potential to save the lives of a very vulnerable group of patients and also to reduce transmission of TB. The new regimen is based on existing widely used drugs so could be readily implemented in sub-Saharan Africa. The trial team is also maintaining close links with policymakers in the region, as well as global bodies involved in TB control, to ensure that findings are rapidly communicated to decision-makers and inform policy and practice.

Impact

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crucial in

widening African

children’s access

to antiretrovirals

Bringing antiretroviral drugs to children

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The CHAPAS trials have ensured that many more children with HIV have benefited
from life-saving antiretrovirals.

EDCTP portfolio: HIV & HIV-associated infections

The challenge

Although care for people living with HIV has improved markedly in recent years, around a quarter only start treatment when their CD4 white blood cell numbers have been severely depleted. This places them at greatly increased risk of other infections, including TB. As many as 30% of people living with HIV succumb to TB, accounting for 19% of global TB mortality.

HIV infections increase the risk of active TB disease, and also lead to reduced concentrations of TB drugs in the bloodstream, owing to abnormalities in the adsorption of TB drugs. Antiretroviral therapy can also interfere with the action of TB drugs. Conversely, antiretroviral therapy can also trigger a potentially deadly exaggerated immune response to TB (immune reconstitution inflammatory syndrome, IRIS).

watermark

The DATURA trial is evaluating an intensified TB treatment regimen designed to address these challenges in people living with HIV and with low CD4 cell counts.

Recent trials have confirmed the safety of high doses of the key TB drug rifampicin. The DATURA trial is combining high-dose rifampicin with a higher than usual dose of isoniazid. The trial team will liaise with the EDCTP-funded INTENSE TBM project, which is using high-dose rifampicin to reduce mortality associated with tuberculosis meningitis.

The trial regimen will also incorporate a corticosteroid (prednisone), shown in the EDCTP-funded PREDART trial to reduce the risk of IRIS reactions in patients starting antiretroviral treatment.

The trial will compare the intensified approach – 8 weeks of high-dose anti-TB drugs followed by 16 weeks of classical treatment, plus 6 weeks of prednisone – with the standard 24-week TB treatment regime. The trial will include nearly 1,000 patients from all four regions of sub-Saharan Africa, generating definitive evidence on the efficacy and safety of this new approach.

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 DATURA trial is addressing a critical health issue in sub-Saharan Africa. If intensified treatment is shown to be more effective, it would have the potential to save the lives of a very vulnerable group of patients and also to reduce transmission of TB. The new regimen is based on existing widely used drugs so could be readily implemented in sub-Saharan Africa. The trial team is also maintaining close links with policymakers in the region, as well as global bodies involved in TB control, to ensure that findings are rapidly communicated to decision-makers and inform policy and practice.

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

L’homme RF et al. Nevirapine, stavudine and lamivudine pharmacokinetics in African children on paediatric fixed-dose combination tablets. AIDS. 2008;22(5):557–65.

Mulenga V et al. Abacavir, zidovudine, or stavudine as paediatric tablets for African HIVinfected children (CHAPAS-3): an open-label, parallel-group, randomised controlled trial. Lancet Infect Dis. 2016;16(2):169–79.

WHO. Guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. 2010.

WHO. Consolidated guidelines on the use of antiretroviral drugs
for treating and preventing

HIV infection: Recommendations for a public health approach
(second edition). 2016

Projects: Children with HIV in Africa Pharmacokinetics and Adherence of Simple Antiretroviral Regimens (CHAPAS): CHAPAS-1 and -3

Project lead: Professor Chifumbe Chintu, University Teaching Hospital, Zambia (CHAPAS-1); Dr Veronica Mulenga, University Teaching Hospital, Zambia (CHAPAS-3)

Target population(s): Children with HIV

Sample size: 71 (CHAPAS-1); 480 (CHAPAS-3)

Countries involved: Ireland, the Netherlands, the UK, the USA, Zambia (CHAPAS-1); Uganda, Zambia (CHAPAS-3)

Project duration: 2005–2009 (CHAPAS-1); 2010 –2011 (CHAPAS-3)

EDCTP funding: €1.2M (CHAPAS-1); €4.6M (CHAPAS-3)

Total project funding: €1.2M (CHAPAS-1); €5.0M