Dr Stephanus Malherbe

South Africa

EDCTP portfolio: Career Development Fellowships

Dr Stephanus Malherbe aims to facilitate the discovery of biomarkers which evaluate successful TB treatment regardless of treatment duration and would allow for individualised treatment duration.

Lung imaging to evaluate 4 and 6 months treatment of pulmonary TB

Shortening of tuberculosis (TB) treatment to 16 weeks or shorter is a main priority of TB research to decrease cost, improve treatment adherence and decrease the development of drug resistance. Clinical trials of treatment shortening have thus far all failed but have consistently found 80-85% treatment success rates in the 16-week arms. This suggests that the majority of patients are cured within 16 weeks. The challenge is to identify these patients, so for this subset treatment shortening could be successfully accomplished.

The challenge

Identification of said patients needs a better understanding of biomarkers to monitor the treatment of pulmonary tuberculosis. Recently, 18F-Fluorodeoxyglucose Positron Emission Tomography / Computed tomography (PET/CT) has shown promise as a tool to stratify risk, monitor response and provide insight into the dynamics of Mtb versus host interaction during TB treatment.

Dr Malherbe conducts the Evaluate 4mTB study as a substudy of the Predict-TB trial. The parent study’s aim is to demonstrate that the 72-weeks (18-months) treatment success rate of standard treatment stopped after 16 weeks is not inferior to treatment stopped after 24 weeks, in subjects classified as low risk by new criteria, based on PET/CT scans at baseline and week 4.

Dr Malherbe’s study aims to validate and optimise the functional and anatomical characteristics, previously identified by 18F-FDG PET/CT scans on patients with pulmonary TB (with a focus on scans at 16 and 24 weeks), and use this information to provide insight into the dynamics of Mtb versus host interaction, serve as a prognostic indicator and facilitate the discovery of biomarkers to monitor and understand treatment response during 16 and 24 week treatment courses. In this prospective randomised non-inferiority phase IIb trial, he and his team recruit and follow up 516 patients with pulmonary TB for 72 weeks, and perform PET/CT scans at Dx, 4 weeks and 16 weeks. Those that meet early treatment criteria, will be randomised to a treatment of either 16 or 24 weeks.

The project

As scans at the end of treatment are more accurate than early treatment scans and provide a better understanding of lung pathology after shortened treatment, this should facilitate the discovery of biomarkers to evaluate the end-of-treatment status of the TB infection in the lung, regardless of treatment duration. This, in turn, would be a major step towards easy and affordable tests to allow individualised treatment duration.

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

Shortening of tuberculosis (TB) treatment to 16 weeks or shorter is a main priority of TB research to decrease cost, improve treatment adherence and decrease the development of drug resistance. Clinical trials of treatment shortening have thus far all failed but have consistently found 80-85% treatment success rates in the 16-week arms. This suggests that the majority of patients are cured within 16 weeks. The challenge is to identify these patients, so for this subset treatment shortening could be successfully accomplished.

Identification of said patients needs a better understanding of biomarkers to monitor the treatment of pulmonary tuberculosis. Recently, 18F-Fluorodeoxyglucose Positron Emission Tomography / Computed tomography (PET/CT) has shown promise as a tool to stratify risk, monitor response and provide insight into the dynamics of Mtb versus host interaction during TB treatment.

Dr Malherbe conducts the Evaluate 4mTB study as a substudy of the Predict-TB trial. The parent study’s aim is to demonstrate that the 72-weeks (18-months) treatment success rate of standard treatment stopped after 16 weeks is not inferior to treatment stopped after 24 weeks, in subjects classified as low risk by new criteria, based on PET/CT scans at baseline and week 4.

Dr Malherbe’s study aims to validate and optimise the functional and anatomical characteristics, previously identified by 18F-FDG PET/CT scans on patients with pulmonary TB (with a focus on scans at 16 and 24 weeks), and use this information to provide insight into the dynamics of Mtb versus host interaction, serve as a prognostic indicator and facilitate the discovery of biomarkers to monitor and understand treatment response during 16 and 24 week treatment courses. In this prospective randomised non-inferiority phase IIb trial, he and his team recruit and follow up 516 patients with pulmonary TB for 72 weeks, and perform PET/CT scans at Dx, 4 weeks and 16 weeks. Those that meet early treatment criteria, will be randomised to a treatment of either 16 or 24 weeks.

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.

As scans at the end of treatment are more accurate than early treatment scans and provide a better understanding of lung pathology after shortened treatment, this should facilitate the discovery of biomarkers to evaluate the end-of-treatment status of the TB infection in the lung, regardless of treatment duration. This, in turn, would be a major step towards easy and affordable tests to allow individualised treatment duration.

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