Dr Charles Drago Kato

Uganda

EDCTP portfolio: Career Development Fellowships

Dr Charles Drago Kato aims to establish biomarkers for diagnosing late-stage trypanosomiasis.

Novel plasma biomarkers for diagnosing stage of sleeping sickness patients

Sleeping sickness progresses in two stages, the early stage with parasites in blood and the late stage in which parasites invade the central nervous system. Drug treatment for both early- and late-stage disease differs. Therefore, it is mandatory to first determine the disease stage.

However, the current staging criterion using cerebrospinal fluid relies on an invasive lumbar puncture that is also required to monitor treatment efficacy. Since initial disease diagnosis is done using blood, identification of plasma biomarkers to replace current criteria for the evaluation of stage and treatment efficacy is of utmost urgency. The challenge is to establish the clinical utility of several plasma biomarkers.

The challenge

Previously, novel plasma biomarkers were identified with proteomics methods. The markers discriminate late stage from early-stage patients for Trypanosoma brucei rhodesiense. The clinical utility of these biomarkers is not yet known and it is not clear if these markers would also apply to T. b. gambiense.

In this study, Dr Kato and his team propose to carry out a clinical validation of these novel plasma biomarkers as stage diagnostic markers. We shall conduct a retrospective study using archived samples from the trypanosomiasis biobank at Makerere University to assess disease staging potential. Patient samples will be selected that were recruited at Lwala hospital (North Eastern Uganda) for T. b. rhodesiense, and Omugo (West Nile) for T. b. gambiense. Through proteomics methods, he aims to find out whether markers identified for T. b. rhodesiense also apply to T. b. gambiense. Clinical validation of identified markers will involve analysis as a single biomarker and as a panel of two or more analytes to determine the best predictor of late-stage disease.

The project

Successful identification of biomarkers will form a basis for translation into field-based dipstick assays for disease staging and inform policy regarding disease staging. This will greatly improve patient management through the abolition of the mandatory requirement of an invasive lumbar puncture which is painful to patients.

Furthermore, the successful execution of this project will build capacity at Makerere University by offering training of critical skills to junior researchers.

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

Sleeping sickness progresses in two stages, the early stage with parasites in blood and the late stage in which parasites invade the central nervous system. Drug treatment for both early- and late-stage disease differs. Therefore, it is mandatory to first determine the disease stage.

However, the current staging criterion using cerebrospinal fluid relies on an invasive lumbar puncture that is also required to monitor treatment efficacy. Since initial disease diagnosis is done using blood, identification of plasma biomarkers to replace current criteria for the evaluation of stage and treatment efficacy is of utmost urgency. The challenge is to establish the clinical utility of several plasma biomarkers.

Previously, novel plasma biomarkers were identified with proteomics methods. The markers discriminate late stage from early-stage patients for Trypanosoma brucei rhodesiense. The clinical utility of these biomarkers is not yet known and it is not clear if these markers would also apply to T. b. gambiense.

In this study, Dr Kato and his team propose to carry out a clinical validation of these novel plasma biomarkers as stage diagnostic markers. We shall conduct a retrospective study using archived samples from the trypanosomiasis biobank at Makerere University to assess disease staging potential. Patient samples will be selected that were recruited at Lwala hospital (North Eastern Uganda) for T. b. rhodesiense, and Omugo (West Nile) for T. b. gambiense. Through proteomics methods, he aims to find out whether markers identified for T. b. rhodesiense also apply to T. b. gambiense. Clinical validation of identified markers will involve analysis as a single biomarker and as a panel of two or more analytes to determine the best predictor of late-stage disease.

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.

Successful identification of biomarkers will form a basis for translation into field-based dipstick assays for disease staging and inform policy regarding disease staging. This will greatly improve patient management through the abolition of the mandatory requirement of an invasive lumbar puncture which is painful to patients.

Furthermore, the successful execution of this project will build capacity at Makerere University by offering training of critical skills to junior researchers.

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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