The AMBITION-cm trial will confirm whether a simple treatment for a potentially lethal fungal infection is suitable for use in Africa.

Improving treatment of HIV-associated meningitis

Early mortality from HIV is much higher in Africa than in high-income countries. Up to one in five HIV-related deaths in Africa are attributable to an opportunistic fungal infection, Cryptococcus, which can cause a lethal meningitis. Cryptococcal meningitis is responsible for around 500,000 deaths a year in sub-Saharan Africa.

The most widely used treatment in Africa, fluconazole, is of limited effectiveness – mortality is still higher than 50%. A superior alternative treatment, amphotericin B, is rarely used in African settings because it has to be given over two weeks and can trigger severe toxic reactions so patients require specialist monitoring.

The challenge

The AMBITION-cm team has been evaluating an alternative formulation of amphotericin B, delivered in tiny lipid-based packages (liposomes), which would be more suitable for resource-poor settings. A phase II study showed that a single high dose of liposomal amphotericin B was safe and early antifungal responses were as good as those seen with the traditional two-week course.

Building on these promising findings, the phase III AMBITION-cm trial is comparing a one-week course of amphotericin B with single high-dose liposomal amphotericin B. The trial, taking place in five African countries, will determine whether single-dose liposomal amphotericin B is as good as the traditional two-week course at reducing mortality at 10 weeks.

The project

The AMBITION-cm trial is the largest HIV-associated cryptococcal meningitis treatment trial ever undertaken. If the encouraging phase II results are confirmed, a simple amphotericin B-based therapy could transform treatment of one of the most important causes of HIV-associated mortality in Africa.

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

Early mortality from HIV is much higher in Africa than in high-income countries. Up to one in five HIV-related deaths in Africa are attributable to an opportunistic fungal infection, Cryptococcus, which can cause a lethal meningitis. Cryptococcal meningitis is responsible for around 500,000 deaths a year in sub-Saharan Africa.

The most widely used treatment in Africa, fluconazole, is of limited effectiveness – mortality is still higher than 50%. A superior alternative treatment, amphotericin B, is rarely used in African settings because it has to be given over two weeks and can trigger severe toxic reactions so patients require specialist monitoring.

The AMBITION-cm team has been evaluating an alternative formulation of amphotericin B, delivered in tiny lipid-based packages (liposomes), which would be more suitable for resource-poor settings. A phase II study showed that a single high dose of liposomal amphotericin B was safe and early antifungal responses were as good as those seen with the traditional two-week course.

Building on these promising findings, the phase III AMBITION-cm trial is comparing a one-week course of amphotericin B with single high-dose liposomal amphotericin B. The trial, taking place in five African countries, will determine whether single-dose liposomal amphotericin B is as good as the traditional two-week course at reducing mortality at 10 weeks.

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 AMBITION-cm trial is the largest HIV-associated cryptococcal meningitis treatment trial ever undertaken. If the encouraging phase II results are confirmed, a simple amphotericin B-based therapy could transform treatment of one of the most important causes of HIV-associated mortality in Africa.

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

Projects: CAPRISA 018 study

Project lead: Professor Salim Abdool Karim, Centre for the AIDS Programme of Research in South Africa, South Africa

Countries involvedFrance, The Netherlands, South Africa

Target population(s): Women

Year funded: 2017

EDCTP funding: €9.8 M

Total project funding: €11.4M plus donation of study drugs

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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