Publications

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

Dr Michael Frimpong

Ghana

EDCTP portfolio: Career Development Fellowships

Dr Michael Frimpong explores the potential of recombinase polymerase amplification (RPA) as a tool for the rapid diagnosis of Mycobacterium ulcerans infections.

Rapid detection of Buruli ulcer

Buruli ulcer is a neglected tropical disease, principally in West African countries, that causes large disfiguring ulcers. It is caused by infection with Mycobacterium ulcerans in the subcutaneous layer of the skin. There are no proven preventive strategies against BU, so early diagnosis and treatment are crucial to avoid physical disabilities that occur if not managed early.

Polymerase chain reaction (PCR) for the IS2404 repeat sequence of M. ulcerans plasmid DNA is regarded as the gold standard for case confirmation due to its high sensitivity and specificity but its use is limited by high cost and the need for a sophisticated laboratory setup, not usually available in resource-poor endemic communities. Research to develop a point-of-care diagnostic test is a major priority.

The challenge

Dr Frimpong’s research explores the potential of recombinase polymerase amplification (RPA) as a tool for the diagnosis of Buruli ulcer. RPA has emerged as a novel isothermal technology for use in molecular diagnosis of infectious diseases. The study has several goals. The first is to optimise an RPA assay for the diagnosis of Buruli ulcer and test its sensitivity and specificity in clinical samples compared with the gold standard, PCR for IS2404. This is followed by an assessment of the feasibility and acceptability of the technique for implementation in resource-limited health facilities and laboratories by health staff. The development of a lateral flow RPA detection system will be explored and initiated.

His preliminary investigations in the laboratory have shown great promise of RPA to detect M. ulcerans DNA by targeting the IS2404 insertion sequence, the same target used in PCR diagnostics. Initial results have shown that DNA from multiple strains of M. ulcerans (Mu1082, Mu5114, Mu912, and Mu560) can be accurately detected with this assay. However, this is not the case for other mycobacteria (e.g. M. tuberculosis, M. chelonae, M. avium, M. marinum, M. celatum and M. vaccae).

The project

Dr Frimpong expects that the project will lead to the development of a point-of-care RPA assay for the detection of M. ulcerans in clinical samples.

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

Buruli ulcer is a neglected tropical disease, principally in West African countries, that causes large disfiguring ulcers. It is caused by infection with Mycobacterium ulcerans in the subcutaneous layer of the skin. There are no proven preventive strategies against BU, so early diagnosis and treatment are crucial to avoid physical disabilities that occur if not managed early.

Polymerase chain reaction (PCR) for the IS2404 repeat sequence of M. ulcerans plasmid DNA is regarded as the gold standard for case confirmation due to its high sensitivity and specificity but its use is limited by high cost and the need for a sophisticated laboratory setup, not usually available in resource-poor endemic communities. Research to develop a point-of-care diagnostic test is a major priority.

Dr Frimpong’s research explores the potential of recombinase polymerase amplification (RPA) as a tool for the diagnosis of Buruli ulcer. RPA has emerged as a novel isothermal technology for use in molecular diagnosis of infectious diseases. The study has several goals. The first is to optimise an RPA assay for the diagnosis of Buruli ulcer and test its sensitivity and specificity in clinical samples compared with the gold standard, PCR for IS2404. This is followed by an assessment of the feasibility and acceptability of the technique for implementation in resource-limited health facilities and laboratories by health staff. The development of a lateral flow RPA detection system will be explored and initiated.

His preliminary investigations in the laboratory have shown great promise of RPA to detect M. ulcerans DNA by targeting the IS2404 insertion sequence, the same target used in PCR diagnostics. Initial results have shown that DNA from multiple strains of M. ulcerans (Mu1082, Mu5114, Mu912, and Mu560) can be accurately detected with this assay. However, this is not the case for other mycobacteria (e.g. M. tuberculosis, M. chelonae, M. avium, M. marinum, M. celatum and M. vaccae).

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.

Dr Frimpong expects that the project will lead to the development of a point-of-care RPA assay for the detection of M. ulcerans in clinical samples.

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