EDCTP portfolio: Career Development Fellowships
index
Dr Yaya Kassogue investigates enzymes that influence ARV drug metabolism and thus treatment response.
Pharmacogenetics of ART
The introduction of highly active antiretroviral therapy reduced the morbidity and mortality related to HIV infection. However, the occurrence in certain patients of invalidating side effects or resistance related to antiretroviral treatment (ART) may be a source of nonadherence and results in an inadequate response.
The challenge
The differences in treatment response observed in patients could be due to various factors such as age, gender, and ethnicity. However, genetic factors also play a significant role in the variability of the response to treatment. Thus, interindividual differences in DNA sequence as a result of single nucleotide polymorphisms (SNP) may explain the variability of therapeutic responses.
Dr Kassogue will focus on the pharmacogenetics aspects of ART treatment and will investigate the impact of selected SNPs from three major classes of drug metabolising enzymes. These most relevant enzymatic classes influencing drug metabolism are the cytochrome P450, the multidrug resistance gene-1, and the glutathione S-transferase.
The project
In addition to supporting the development of the research skills of the fellow, the project may further insight into genetic factors influencing ART treatment response. This may contribute to avoid invalidating side effects in certain patients.
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 introduction of highly active antiretroviral therapy reduced the morbidity and mortality related to HIV infection. However, the occurrence in certain patients of invalidating side effects or resistance related to antiretroviral treatment (ART) may be a source of nonadherence and results in an inadequate response.
The differences in treatment response observed in patients could be due to various factors such as age, gender, and ethnicity. However, genetic factors also play a significant role in the variability of the response to treatment. Thus, interindividual differences in DNA sequence as a result of single nucleotide polymorphisms (SNP) may explain the variability of therapeutic responses.
Dr Kassogue will focus on the pharmacogenetics aspects of ART treatment and will investigate the impact of selected SNPs from three major classes of drug metabolising enzymes. These most relevant enzymatic classes influencing drug metabolism are the cytochrome P450, the multidrug resistance gene-1, and the glutathione S-transferase.
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.
In addition to supporting the development of the research skills of the fellow, the project may further insight into genetic factors influencing ART treatment response. This may contribute to avoid invalidating side effects in certain patients.
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