The INTENSE-TBM study will provide the first data on whether intensified treatment of tuberculous meningitis – TB infection of the brain – reduces mortality and long-term disability.

Improving treatments for TB-associated meningitis

Although the TB bacterium is mainly found in the lungs, it can also invade the central nervous system, causing a potentially lethal form of meningitis in the brain. Tuberculous meningitis is particularly common in young children, and has a high mortality rate (30%). Mortality is much higher in patients with HIV, particularly when they are infected with drug-resistant strains of TB. In addition, around half of survivors are affected by long-term disabilities.

Treatment of tuberculous meningitis is complicated as the blood–brain barrier restricts access of anti-TB drugs to infected tissues. In addition, despite its severity, there is relatively little evidence on the optimum treatment of tuberculous meningitis.

The challenge

The INTENSE-TBM study is evaluating a revised, more intensive treatment of patients with tuberculous meningitis, including those with HIV infections. The first week’s treatment will include high-dose intravenous rifampicin, which does not cross the blood–brain barrier well, and linezolid, an anti-TB drug that shows good uptake into the brain, plus other anti-TB drugs and corticosteroids. For the next two months, treatment switches to an oral regime, followed by a simplified antibiotic regime up to seven months. The trial will also test whether daily aspirin is beneficial, by reducing tissue-damaging inflammation.

For patients with HIV infections, triple antiretroviral therapy will begin four weeks after the start of treatment for tuberculous meningitis. Dexamethasone will also be given during the first four weeks of antiretroviral treatment, to reduce the risk of immune reconstitution inflammatory syndrome (IRIS) – when a recovering immune system launches a powerful response against TB infections.

The study will also examine how combined use of antiretroviral and anti-TB medicines affects their metabolism in the body. 

The project

The INTENSE-TBM study will answer key questions in treatment of tuberculous meningitis, which has scarcely changed in decades. It will assess the impact of more intensive treatment on mortality and the likelihood of longer-term disability, and generate data on a tailored regimen specific for those infected with HIV.

Impact


crucial in

widening African

children’s access

to antiretrovirals

Bringing antiretroviral drugs to children

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 the TB bacterium is mainly found in the lungs, it can also invade the central nervous system, causing a potentially lethal form of meningitis in the brain. Tuberculous meningitis is particularly common in young children, and has a high mortality rate (30%). Mortality is much higher in patients with HIV, particularly when they are infected with drug-resistant strains of TB. In addition, around half of survivors are affected by long-term disabilities.

Treatment of tuberculous meningitis is complicated as the blood–brain barrier restricts access of anti-TB drugs to infected tissues. In addition, despite its severity, there is relatively little evidence on the optimum treatment of tuberculous meningitis.

The INTENSE-TBM study is evaluating a revised, more intensive treatment of patients with tuberculous meningitis, including those with HIV infections. The first week’s treatment will include high-dose intravenous rifampicin, which does not cross the blood–brain barrier well, and linezolid, an anti-TB drug that shows good uptake into the brain, plus other anti-TB drugs and corticosteroids. For the next two months, treatment switches to an oral regime, followed by a simplified antibiotic regime up to seven months. The trial will also test whether daily aspirin is beneficial, by reducing tissue-damaging inflammation.

For patients with HIV infections, triple antiretroviral therapy will begin four weeks after the start of treatment for tuberculous meningitis. Dexamethasone will also be given during the first four weeks of antiretroviral treatment, to reduce the risk of immune reconstitution inflammatory syndrome (IRIS) – when a recovering immune system launches a powerful response against TB infections.

The study will also examine how combined use of antiretroviral and anti-TB medicines affects their metabolism in the body. 

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 INTENSE-TBM study will answer key questions in treatment of tuberculous meningitis, which has scarcely changed in decades. It will assess the impact of more intensive treatment on mortality and the likelihood of longer-term disability, and generate data on a tailored regimen specific for those infected with HIV.

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

About us

The European & Developing Countries Clinical Trials Partnership (EDCTP) is a public–public partnership between 14 European and 16 African countries, supported by the European Union. EDCTP’s vision is to reduce the individual, social and economic burden of poverty-related infectious diseases by affecting sub-Saharan Africa. EDCTP’s mission is to accelerate the development of new or improved medicinal products for the identification, treatment and prevention of infectious diseases, including emerging and re-emerging diseases, through pre- and postregistration clinical studies, with emphasis on phase II and III clinical trials. Our approach integrates conduct of research with development of African clinical research capacity and networking. The second EDCTP programme is implemented by the EDCTP Association supported under Horizon 2020, the European Union’s Framework Programme for Research and Innovation.

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