Publications

Funding for clinical research |drugs, vaccines, microbicides, diagnostics | HIV/AIDS, tuberculosis, malaria, other infectious diseases |sub-Saharan Africa

Dr Laurent Dembele

Mali

EDCTP portfolio: Career Development Fellowships

Dr Laurent Dembele aims to establish a screening model for malaria liver-stage infection by Plasmodium vivax and Plasmodium ovale using field-isolated sporozoites from infected mosquitoes.

Field-based screening model for P. vivax and P. ovale malaria infection

Research focusing on Plasmodium vivax and Plasmodium ovale has been severely limited as most malaria control programmes have focused on P. falciparum malaria. However, P. vivax and P. ovale have the unique attribute to cause malaria relapses, resulting from the activation of quiescent hepatic hypnozoites. This hinders global efforts to control and eliminate malaria.

Currently, primaquine is the only licensed drug able to eradicate hypnozoites. However, primaquine is not a well-tolerated drug. The challenge is to develop better drugs.

The challenge

Very few tools are available to support biological studies and screening efforts for P. vivax and P. ovale. There is also no reliable robust culture system for the blood-stage forms of P. vivax and P. ovale, nor for the most closely related simian malaria species, P. cynomolgi. Thus, access to P. vivax and P. ovale is dependent on field isolates. These major obstacles have limited molecular and cellular investigation of P. vivax and P. ovale malaria biology.

An optimised in vitro liver-stage model supporting biological studies and screening efforts which would be easily accessible to all researchers is critically needed to enable the discovery of new drugs. In a first step, the simian parasite, P. cynomolgi which is related to P. vivax, was used to establish an in vitro culture system in which the full liver-stage life-cycle of the parasite including the hypnozoite stage, was recapitulated. It was demonstrated that this system could be used for testing candidate drugs or exploring the liver-stage biology including hypnozoite.

Dr Dembele now aims to accelerate research towards an optimised drug assay to evaluate the anti-hypnozoite activity of candidate drugs. The project comprises field and clinical activities: experimental infection of P. vivax and P. ovale to Anopheles spp in Addis Ababa and Bamako; routine production of sporozoites from P. vivax- and P. ovale-infected mosquitoes. Ultimately, Dr Dembele aims to establish an in vitro optimised malaria liver-stage infection and screening model using field-isolated sporozoites from P. vivax- and P. ovale-infected mosquitoes.

The project

The successful development of a malaria liver-stage infection and screening model for P. vivax- and P. ovale would be an important contribution to more effective malaria control efforts (focused on P. falciparum malaria) as P. vivax and P. ovale have the ability to cause malaria relapses.

Impact


test the safety and efficacy of this new formulation in young children

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

Research focusing on Plasmodium vivax and Plasmodium ovale has been severely limited as most malaria control programmes have focused on P. falciparum malaria. However, P. vivax and P. ovale have the unique attribute to cause malaria relapses, resulting from the activation of quiescent hepatic hypnozoites. This hinders global efforts to control and eliminate malaria.

Currently, primaquine is the only licensed drug able to eradicate hypnozoites. However, primaquine is not a well-tolerated drug. The challenge is to develop better drugs.

Very few tools are available to support biological studies and screening efforts for P. vivax and P. ovale. There is also no reliable robust culture system for the blood-stage forms of P. vivax and P. ovale, nor for the most closely related simian malaria species, P. cynomolgi. Thus, access to P. vivax and P. ovale is dependent on field isolates. These major obstacles have limited molecular and cellular investigation of P. vivax and P. ovale malaria biology.

An optimised in vitro liver-stage model supporting biological studies and screening efforts which would be easily accessible to all researchers is critically needed to enable the discovery of new drugs. In a first step, the simian parasite, P. cynomolgi which is related to P. vivax, was used to establish an in vitro culture system in which the full liver-stage life-cycle of the parasite including the hypnozoite stage, was recapitulated. It was demonstrated that this system could be used for testing candidate drugs or exploring the liver-stage biology including hypnozoite.

Dr Dembele now aims to accelerate research towards an optimised drug assay to evaluate the anti-hypnozoite activity of candidate drugs. The project comprises field and clinical activities: experimental infection of P. vivax and P. ovale to Anopheles spp in Addis Ababa and Bamako; routine production of sporozoites from P. vivax- and P. ovale-infected mosquitoes. Ultimately, Dr Dembele aims to establish an in vitro optimised malaria liver-stage infection and screening model using field-isolated sporozoites from P. vivax- and P. ovale-infected mosquitoes.

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 successful development of a malaria liver-stage infection and screening model for P. vivax- and P. ovale would be an important contribution to more effective malaria control efforts (focused on P. falciparum malaria) as P. vivax and P. ovale have the ability to cause malaria relapses.

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