Publications

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

Dr Navisha Dookie

South Africa

EDCTP portfolio: Career Development Fellowships

Dr Navisha Dookie aims to optimise the clinical utility of whole-genome sequencing to enable individualised treatment of patients with drug-resistant TB.

Understanding the genetics of TB-drug resistance for clinical use

Resistance to antituberculosis drugs has emerged as a key public health challenge. The last decade has seen an unprecedented increase in resistance to rifampicin and isoniazid (defined as multidrug resistance) and has been supplanted by additional resistance to fluoroquinolones and second-line injectable agents: amikacin, kanamycin and capreomycin (defined as extensive resistance).

Multidrug-resistant TB and extensively drug-resistant TB (XDR-TB) drive approximately a quarter of the global TB-related mortality, are unsustainably costly to treat and pose a major threat of continued transmission. Current treatment options for XDR-TB fail to cure 30-75% of patients with XDR-TB, contributing to an emerging public health crisis. The first challenge is to improve current diagnostics, which have a limited capacity to detect drug resistance and slow turnaround times.

The challenge

Dr Dookie proposed a study embedded in the CAPRISA 020 Index Study. This study is the first of its kind, utilising the most robust sequencing technology to provide an individualised treatment regimen for patients with drug-resistant TB. In the fellowship study, Dr Dookie will focus on improving understanding of the development of resistance in patients undergoing treatment, optimise the extraction of DNA directly from sputum and assess the contribution of the various pathogen factors that impact on drug-resistant TB outcomes.

The project

The fellowship will translate basic science studies which will improve the utility of sequencing technology to provide a robust real-time diagnostic assay. It will also provide a comprehensive algorithm for the inclusion and exclusion of drugs, based on the clinical relevance of resistance mutations. Moreover, it will improve understanding of the differential pathogenesis and disease outcomes by strain type and thus inform targeted interventions for interrupting transmission. This study may pave the path for new therapeutic and management approaches for drug-resistant TB.

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

Resistance to antituberculosis drugs has emerged as a key public health challenge. The last decade has seen an unprecedented increase in resistance to rifampicin and isoniazid (defined as multidrug resistance) and has been supplanted by additional resistance to fluoroquinolones and second-line injectable agents: amikacin, kanamycin and capreomycin (defined as extensive resistance).

Multidrug-resistant TB and extensively drug-resistant TB (XDR-TB) drive approximately a quarter of the global TB-related mortality, are unsustainably costly to treat and pose a major threat of continued transmission. Current treatment options for XDR-TB fail to cure 30-75% of patients with XDR-TB, contributing to an emerging public health crisis. The first challenge is to improve current diagnostics, which have a limited capacity to detect drug resistance and slow turnaround times.

Dr Dookie proposed a study embedded in the CAPRISA 020 Index Study. This study is the first of its kind, utilising the most robust sequencing technology to provide an individualised treatment regimen for patients with drug-resistant TB. In the fellowship study, Dr Dookie will focus on improving understanding of the development of resistance in patients undergoing treatment, optimise the extraction of DNA directly from sputum and assess the contribution of the various pathogen factors that impact on drug-resistant TB outcomes.

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 fellowship will translate basic science studies which will improve the utility of sequencing technology to provide a robust real-time diagnostic assay. It will also provide a comprehensive algorithm for the inclusion and exclusion of drugs, based on the clinical relevance of resistance mutations. Moreover, it will improve understanding of the differential pathogenesis and disease outcomes by strain type and thus inform targeted interventions for interrupting transmission. This study may pave the path for new therapeutic and management approaches for drug-resistant TB.

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