Publications

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

Dr Anzaan Dippenaar

South Africa

EDCTP portfolio: Career Development Fellowships

Dr Anzaan Dippenaar aims to guide treatment of rifampicin-resistant TB through early drug susceptibility testing.

Comprehensive genetic profiles of drug resistance

TB treatment strategies rely on the use of combination therapy to reduce the risk of antibiotic selection of resistance and thus to protect the limited repertoire of anti-tuberculosis drugs available.

Optimising the treatment regimen for patients with drug-resistant tuberculosis is dependent on knowledge of genetically encoded resistance. M. tuberculosis develops drug resistance through mutations in target genes. Identifying these mutations creates a drug susceptibility profile of the infecting pathogen.

Sequencing the whole genome of M. tuberculosis offers the opportunity to identify mutations conferring drug-resistance in all genes known to be involved in resistance. This technology has already been implemented in the United Kingdom and in the USA to guide patient management, diagnostic policy and surveillance. In South Africa, whole-genome sequencing has been used to describe the epidemiology of extensively drug-resistant tuberculosis with particular emphasis on transmission and the evolution of resistance. This technique has also questioned the reliability of routine testing for drug susceptibility in high-throughput laboratories.

The challenge

Dr Dippenaar proposed to harness the resolution of whole-genome sequencing to provide comprehensive genetic drug resistance profiles on all rifampicin-resistant tuberculosis isolates from patients resident within the Western Cape Province. The objective is to provide clinicians with these profiles in such a way that informed therapy changes can be made at their discretion to improve treatment outcome.

The project

Successfully establishing the genetic drug resistance profiles of all rifampicin-resistant tuberculosis isolates will assist the case management of patients with drug-resistant tuberculosis, enabling doctors to make informed therapy changes and improve outcomes.

The data generated by whole-genome sequencing will also enable to longitudinally measure the impact of policy changes on the drug-resistant tuberculosis epidemic.

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

TB treatment strategies rely on the use of combination therapy to reduce the risk of antibiotic selection of resistance and thus to protect the limited repertoire of anti-tuberculosis drugs available.

Optimising the treatment regimen for patients with drug-resistant tuberculosis is dependent on knowledge of genetically encoded resistance. M. tuberculosis develops drug resistance through mutations in target genes. Identifying these mutations creates a drug susceptibility profile of the infecting pathogen.

Sequencing the whole genome of M. tuberculosis offers the opportunity to identify mutations conferring drug-resistance in all genes known to be involved in resistance. This technology has already been implemented in the United Kingdom and in the USA to guide patient management, diagnostic policy and surveillance. In South Africa, whole-genome sequencing has been used to describe the epidemiology of extensively drug-resistant tuberculosis with particular emphasis on transmission and the evolution of resistance. This technique has also questioned the reliability of routine testing for drug susceptibility in high-throughput laboratories.

Dr Dippenaar proposed to harness the resolution of whole-genome sequencing to provide comprehensive genetic drug resistance profiles on all rifampicin-resistant tuberculosis isolates from patients resident within the Western Cape Province. The objective is to provide clinicians with these profiles in such a way that informed therapy changes can be made at their discretion to improve treatment outcome.

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.

Successfully establishing the genetic drug resistance profiles of all rifampicin-resistant tuberculosis isolates will assist the case management of patients with drug-resistant tuberculosis, enabling doctors to make informed therapy changes and improve outcomes.

The data generated by whole-genome sequencing will also enable to longitudinally measure the impact of policy changes on the drug-resistant tuberculosis epidemic.

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