EDCTP portfolio: Career Development Fellowships

Dr Willy Ssengooba evaluates how other methods of treatment monitoring than by sputum culture may predict outcomes of a shorter MDR-TB treatment regimen.

New ways to predict MDR-TB treatment outcome early

Effective treatment monitoring is vital not only for proper patient management but also for preventing the unnecessary continuation of failing treatment and emergence of more drug-resistant Mycobacterium tuberculosis (Mtb). Treatment monitoring by sputum culture is the gold standard for TB treatment. However, this method has several problems, including high operational cost and long turnaround time.

The challenge is to develop better alternatives which will protect the currently effective drugs and streamline the development of new drugs for multi-drug resistant tuberculosis (MDR-TB).

The challenge

Dr Ssengooba proposes to evaluate the effectiveness – compared with culture colony forming units (CFUs) determination – of alternative methods for measuring the response to therapy during the initial 16 weeks of MDR-TB treatment. These methods will be analysed to determine how well they predict MDR-TB patient treatment outcome.

A prospective study will enrol patients 18 years of age or older and diagnosed with MDR-TB according to local standards. Two sputum samples, a spot and an overnight sample, will be taken at weeks 0, 1, 2, 3, 4, 5, 6, 7, 8 and once during month 3 and 4. Follow-up will be active during the intensive phase and passive during the continuation phase up to 18 months of MDR-TB treatment to document treatment outcomes.

Samples will be pooled and homogenised and divided into three portions. Portion one will be used for respectively, 1) FDA- treated AFB smear microscopy, 2) PMA-Xpert/ULTRA assay, and 3) liquid culture for Mtb-TTP. Portion two will be used for 16s rRNA detection in an MBLA assay and portion three for CFUs/mL determination. Data will be analysed for correlation of the results of the alternative methods with results based on reducing culture CFUs.

The project

Potentially, this study may validate alternative methods of monitoring MDR-TB treatment response in resource-limited settings. Allowing quicker decision making, alternative ways of monitoring may help to protect the available treatment regimens and novel TB drugs, improve the efficiency of phase II trials/treatment regimens and lead to reduced delayed-results costs in the development of new MDR-TB drugs.

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

Effective treatment monitoring is vital not only for proper patient management but also for preventing the unnecessary continuation of failing treatment and emergence of more drug-resistant Mycobacterium tuberculosis (Mtb). Treatment monitoring by sputum culture is the gold standard for TB treatment. However, this method has several problems, including high operational cost and long turnaround time.

The challenge is to develop better alternatives which will protect the currently effective drugs and streamline the development of new drugs for multi-drug resistant tuberculosis (MDR-TB).

Dr Ssengooba proposes to evaluate the effectiveness – compared with culture colony forming units (CFUs) determination – of alternative methods for measuring the response to therapy during the initial 16 weeks of MDR-TB treatment. These methods will be analysed to determine how well they predict MDR-TB patient treatment outcome.

A prospective study will enrol patients 18 years of age or older and diagnosed with MDR-TB according to local standards. Two sputum samples, a spot and an overnight sample, will be taken at weeks 0, 1, 2, 3, 4, 5, 6, 7, 8 and once during month 3 and 4. Follow-up will be active during the intensive phase and passive during the continuation phase up to 18 months of MDR-TB treatment to document treatment outcomes.

Samples will be pooled and homogenised and divided into three portions. Portion one will be used for respectively, 1) FDA- treated AFB smear microscopy, 2) PMA-Xpert/ULTRA assay, and 3) liquid culture for Mtb-TTP. Portion two will be used for 16s rRNA detection in an MBLA assay and portion three for CFUs/mL determination. Data will be analysed for correlation of the results of the alternative methods with results based on reducing culture CFUs.

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.

Potentially, this study may validate alternative methods of monitoring MDR-TB treatment response in resource-limited settings. Allowing quicker decision making, alternative ways of monitoring may help to protect the available treatment regimens and novel TB drugs, improve the efficiency of phase II trials/treatment regimens and lead to reduced delayed-results costs in the development of new MDR-TB drugs.

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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