This publication uses cookies

We use functional and analytical cookies to improve our website. In addition, third parties place tracking cookies to display personalised advertisements on social media. By clicking accept you consent to the placement of these cookies.

EDCTP portfolio: EDCTP/AREF Preparatory Fellowships

Dr Hamdan Abualbasher aims to determine the pharmacokinetics of rifampicin in patients with pulmonary TB and MDR-TB, by training at the University of Cape Town, South Africa, and conducting a study at the Al-Neelain University, Sudan.

How pharmacogenomics affect the pharmacokinetics of first-line TB drugs

The challenge is to fight multiple-drug-resistant tuberculosis. Mycobacterium tuberculosis can become resistant to multiple drugs resulting in MDR-TB, which complicates the patient’s condition and affects the disease course with very poor prognosis.

One of the causes of resistance may be low bioavailability of anti-tuberculosis drugs. Variation of the bioavailability of anti-tuberculosis drugs may be owed to polymorphisms of some drug transporters genes that control drug absorption and secretion. Some of these gene polymorphisms are widely prevalent among Sub-Saharan African populations and some are not investigated.

The challenge

Dr Abualbasher aims to determine the pharmacokinetics of rifampicin in Sudanese patients with pulmonary tuberculosis and MDR-TB. Additionally, he aims to determine the effect of the transporters’ gene polymorphisms on the bioavailability of rifampicin. Thirdly, he wants to determine whether or not rifampicin exposure is associated with a decreased rate of sputum conversion and development of MDR-TB.

The fellow proposed a pilot cohort to follow 70 patients with pulmonary tuberculosis. Sputum will be examined also by GeneXpert assay to rule out any possibility of rifampicin resistance or MDR at the time of diagnosis. DNA sequencing for M. tuberculosis will also be done to make sure there are no secondary infections by other MDR-TB bacteria. At 2, 5 and 6 months after starting anti-tuberculosis drugs, sputum microscopy and culture will be done to differentiate those who developed MDR-TB and those who are drug-susceptible. Blood will be collected from the patients to isolate DNA. Genotyping will be done in selected transporters’ gene by PCR-RFLP and for others by DNA sequencing. Blood samples will be collected at 1, 3 and 8 hours from taking the drugs just once for rifampicin assay.

Pharmacokinetic analysis and population modelling will be done at the University of Cape Town in collaboration with Professor Helen McIlleron and Dr Paolo Denti. Patients will be recruited from Bashier University hospital which is affiliated to the fellow’s home organisation the Al-Neelain University in Sudan.

The project

The study will have direct clinical and policy implications which will contribute to better clinical and epidemiological outcomes for pulmonary tuberculosis. The findings of this pilot study are expected to lead to a bigger sample size study with the development of a simulation model that tested against higher rifampicin doses for those with alleles that pose a risk.

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 challenge is to fight multiple-drug-resistant tuberculosis. Mycobacterium tuberculosis can become resistant to multiple drugs resulting in MDR-TB, which complicates the patient’s condition and affects the disease course with very poor prognosis.

One of the causes of resistance may be low bioavailability of anti-tuberculosis drugs. Variation of the bioavailability of anti-tuberculosis drugs may be owed to polymorphisms of some drug transporters genes that control drug absorption and secretion. Some of these gene polymorphisms are widely prevalent among Sub-Saharan African populations and some are not investigated.

Dr Abualbasher aims to determine the pharmacokinetics of rifampicin in Sudanese patients with pulmonary tuberculosis and MDR-TB. Additionally, he aims to determine the effect of the transporters’ gene polymorphisms on the bioavailability of rifampicin. Thirdly, he wants to determine whether or not rifampicin exposure is associated with a decreased rate of sputum conversion and development of MDR-TB.

The fellow proposed a pilot cohort to follow 70 patients with pulmonary tuberculosis. Sputum will be examined also by GeneXpert assay to rule out any possibility of rifampicin resistance or MDR at the time of diagnosis. DNA sequencing for M. tuberculosis will also be done to make sure there are no secondary infections by other MDR-TB bacteria. At 2, 5 and 6 months after starting anti-tuberculosis drugs, sputum microscopy and culture will be done to differentiate those who developed MDR-TB and those who are drug-susceptible. Blood will be collected from the patients to isolate DNA. Genotyping will be done in selected transporters’ gene by PCR-RFLP and for others by DNA sequencing. Blood samples will be collected at 1, 3 and 8 hours from taking the drugs just once for rifampicin assay.

Pharmacokinetic analysis and population modelling will be done at the University of Cape Town in collaboration with Professor Helen McIlleron and Dr Paolo Denti. Patients will be recruited from Bashier University hospital which is affiliated to the fellow’s home organisation the Al-Neelain University in Sudan.

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 study will have direct clinical and policy implications which will contribute to better clinical and epidemiological outcomes for pulmonary tuberculosis. The findings of this pilot study are expected to lead to a bigger sample size study with the development of a simulation model that tested against higher rifampicin doses for those with alleles that pose a risk.

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