Publications

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

EDCTP portfolio: Career Development Fellowships

Dr Ali Esmail develops and validates an appropriately weighted dynamic clinical prediction rule which can predict the unfavourable or favourable outcome of treatment of MDR-TB.

Predicting unsuccesful MDR-TB treatment response

The emergence of multidrug-resistant TB (MDR-TB) in Africa is a serious public health concern. It is extremely expensive to treat and has high associated mortality, with rates of MDR-TB increasing in countries like South Africa, (32,000 MDR-TB cases were diagnosed last year), the situation is becoming unsustainable with a potential to destabilise TB programmes in Africa.

The introduction of newer agents such as bedaquiline and linezolid have renewed hope in the treatment of drug-resistant TB. However, clinical trials of new treatments for MDR-TB are expensive and prolonged, which delays registration and access to the drug. One of the major challenges in trials of new treatments for MDR-TB is the lack of tools to predict outcomes.

The challenge

As there are no validated biomarker profiles that will identify patients who are likely to have a favourable versus unfavourable outcome, the goal of the proposed project is to evaluate a package of treatment response biomarkers for MDR-TB.

Dr Esmail will aim to formulate a weighted prediction rule incorporating clinical, radiological, mycobacterial, serum and urine biomarkers, which can predict unfavourable from favourable outcomes. The project is nested within the NexT clinical trial, a randomised control trial that is evaluating a new 6-month injection-free regimen for MDR-TB. This South African MRC-funded study will recruit 300 patients with MDR-TB randomised to a WHO-approved or intervention regimen. Data and clinical samples required for the project are available in a biobank.

The project

The successful development and validation of an appropriately weighted dynamic clinical prediction rule that can predict outcome in the treatment of MDR-TB would have an impact on both patient management and the clinical development of new regimens.

TB clinicians would be able to intervene earlier in a patient who is likely to have an unfavourable outcome, as opposed to current standards that use sputum culture, a process which delays such critical decisions by months.

Reduced follow-up times would result in shorter studies. Phase II studies could be conducted to identify the most promising candidate regimens that could then move on to phase III trials in a shorter time. Several trials are currently planned for testing various regimens for the treatment of MDR-TB and with bedaquiline treatment failures starting to emerge the need for new drugs will likely increase over time.

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 emergence of multidrug-resistant TB (MDR-TB) in Africa is a serious public health concern. It is extremely expensive to treat and has high associated mortality, with rates of MDR-TB increasing in countries like South Africa, (32,000 MDR-TB cases were diagnosed last year), the situation is becoming unsustainable with a potential to destabilise TB programmes in Africa.

The introduction of newer agents such as bedaquiline and linezolid have renewed hope in the treatment of drug-resistant TB. However, clinical trials of new treatments for MDR-TB are expensive and prolonged, which delays registration and access to the drug. One of the major challenges in trials of new treatments for MDR-TB is the lack of tools to predict outcomes.

As there are no validated biomarker profiles that will identify patients who are likely to have a favourable versus unfavourable outcome, the goal of the proposed project is to evaluate a package of treatment response biomarkers for MDR-TB.

Dr Esmail will aim to formulate a weighted prediction rule incorporating clinical, radiological, mycobacterial, serum and urine biomarkers, which can predict unfavourable from favourable outcomes. The project is nested within the NexT clinical trial, a randomised control trial that is evaluating a new 6-month injection-free regimen for MDR-TB. This South African MRC-funded study will recruit 300 patients with MDR-TB randomised to a WHO-approved or intervention regimen. Data and clinical samples required for the project are available in a biobank.

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 successful development and validation of an appropriately weighted dynamic clinical prediction rule that can predict outcome in the treatment of MDR-TB would have an impact on both patient management and the clinical development of new regimens.

TB clinicians would be able to intervene earlier in a patient who is likely to have an unfavourable outcome, as opposed to current standards that use sputum culture, a process which delays such critical decisions by months.

Reduced follow-up times would result in shorter studies. Phase II studies could be conducted to identify the most promising candidate regimens that could then move on to phase III trials in a shorter time. Several trials are currently planned for testing various regimens for the treatment of MDR-TB and with bedaquiline treatment failures starting to emerge the need for new drugs will likely increase over time.

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