EDCTP portfolio: Clinical Research & Development Fellowships

Dr Ezenwa James Onyemata aims to apply therapeutic drug monitoring as a tool for improving HIV case management and monitor viral load suppression.

Determining actual drug exposure

The massive global increase in the number of HIV-infected patients on antiretroviral therapy (ART) has resulted in improved quality of life and reduced death rate. The UN aims to achieve 90% viral load (VL) suppression levels among patients on ART by the year 2020.

VL is affected by the level of antiretrovirals (ARVs) within the biological system (among other factors). This can be assessed through therapeutic drug monitoring (TDM). TDM allows for actual drug exposure to be determined, patient compliance gleaned, and provides opportunities for dose adjustment, thus increasing ART efficacy among some populations while avoiding drug-related toxicity. TDM thus could trigger early interventions to address non-adherence or correct low pharmacokinetic levels

The challenge

The aim of the project is foremost the individual research capacity development of the fellow but with a view to applying therapeutic drug monitoring to support the ambitious global goals for HIV control, in particular, viral load suppression.

The fellowship will support Dr Onyemata to become proficient in skills regarding drug profile safety, tolerability, pharmacokinetics and pharmacodynamics for novel compounds. These skills are useful for future involvement in clinical trials phase I and II, one of the goals his institution, the Institute of Human Virology in Nigeria, is pursuing. In addition, TDM can be applied to estimating ARV levels in HIV patients to understand the contribution of ARV bioavailability and dosing to treatment failure. Developing

TDM also requires that the science behind the extraction of ARVs from plasma, peripheral blood mononuclear cells (PBMCs), and hair be understood. Furthermore, the science behind small molecule separation such as choosing mobile phase and chromatographic matrix needs to be understood and optimised for the particular application. Skill in the use of High-Performance Liquid Chromatography and Mass spectrometry is required for detection and quantification of ARV, and associated data processing and interpretation.

The project

The expected impact of the fellowship is the advanced professional development of the fellow who will also contribute to the clinical research capacity of the Nigerian Institute of Human Virology. In future, the availability of personal and institutional expertise in therapeutic drug monitoring may contribute to the inclusion of ARV level monitoring in the HIV treatment guidelines in Nigeria.

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

The massive global increase in the number of HIV-infected patients on antiretroviral therapy (ART) has resulted in improved quality of life and reduced death rate. The UN aims to achieve 90% viral load (VL) suppression levels among patients on ART by the year 2020.

VL is affected by the level of antiretrovirals (ARVs) within the biological system (among other factors). This can be assessed through therapeutic drug monitoring (TDM). TDM allows for actual drug exposure to be determined, patient compliance gleaned, and provides opportunities for dose adjustment, thus increasing ART efficacy among some populations while avoiding drug-related toxicity. TDM thus could trigger early interventions to address non-adherence or correct low pharmacokinetic levels

The aim of the project is foremost the individual research capacity development of the fellow but with a view to applying therapeutic drug monitoring to support the ambitious global goals for HIV control, in particular, viral load suppression.

The fellowship will support Dr Onyemata to become proficient in skills regarding drug profile safety, tolerability, pharmacokinetics and pharmacodynamics for novel compounds. These skills are useful for future involvement in clinical trials phase I and II, one of the goals his institution, the Institute of Human Virology in Nigeria, is pursuing. In addition, TDM can be applied to estimating ARV levels in HIV patients to understand the contribution of ARV bioavailability and dosing to treatment failure. Developing

TDM also requires that the science behind the extraction of ARVs from plasma, peripheral blood mononuclear cells (PBMCs), and hair be understood. Furthermore, the science behind small molecule separation such as choosing mobile phase and chromatographic matrix needs to be understood and optimised for the particular application. Skill in the use of High-Performance Liquid Chromatography and Mass spectrometry is required for detection and quantification of ARV, and associated data processing and interpretation.

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 expected impact of the fellowship is the advanced professional development of the fellow who will also contribute to the clinical research capacity of the Nigerian Institute of Human Virology. In future, the availability of personal and institutional expertise in therapeutic drug monitoring may contribute to the inclusion of ARV level monitoring in the HIV treatment guidelines in Nigeria.

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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