Publications

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

Dr Sean Wasserman

South Africa

EDCTP portfolio: Career Development Fellowships

Dr Sean Wasserman will define the optimal use of linezolid in South African patients with drug-resistant tuberculosis (DR-TB).

Drug-resistant TB: optimising linezolid use in African patients

New evidence-based treatment options are urgently needed to improve the outcomes of drug-resistant tuberculosis. Linezolid improves culture conversion and cure rates in complicated multidrug-resistant (MDR) and extensively drug-resistant TB and has the potential to allow for injection-free regimens for MDR-TB.

Because of its impressive impact on outcomes, linezolid is likely to become a key component of treatment regimens for drug-resistant TB in sub-Saharan Africa. However, it has never been systematically studied in its populations and there are critical knowledge gaps that need to be addressed prior to the expanded use of this important agent.

The challenge

To support the scale-up of safer and more effective drug-resistant TB regimens, the study aims to address several knowledge gaps. First, mitochondrial toxicity associated with long-term use of linezolid leads to treatment-limiting adverse events in over a third of patients. It is unclear whether attempts to reduce this by reducing dosage compromise efficacy and facilitate the emergence of linezolid resistance. Second, the risk of toxicity may potentially be different in patients from sub-Saharan Africa because of high rates of HIV co-infection, different population pharmacokinetics, and unique polymorphisms in mitochondrial DNA (mtDNA). Published reports of linezolid use for drug-resistant TB include outcomes data for only 239 patients worldwide; fewer than 10% of these were HIV-infected and only 55 cases have been reported from Africa.

Dr Wasserman and his team will conduct a large prospective pharmacokinetic and pharmacodynamic (PK/PD) study aimed at defining the optimal use of linezolid in South African patients with DR-TB. The specific objectives of the project are to develop a population PK model of linezolid in South African patients with drug-resistant TB; to determine the effects of linezolid exposure on toxicity, treatment response, and linezolid resistance; and to define the relationships between linezolid PK parameters, functional mitochondrial activity, and clinical toxicity, and explore the association of polymorphisms in mtDNA with the risk of linezolid toxicity in this population.

The project

The study findings will likely inform international guidelines for linezolid use, ultimately translating into improved outcomes for patients with drug-resistant TB.

This project will also enable Dr Wasserman to acquire further skills to lead future clinical and translational studies in the fields of HIV and 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

New evidence-based treatment options are urgently needed to improve the outcomes of drug-resistant tuberculosis. Linezolid improves culture conversion and cure rates in complicated multidrug-resistant (MDR) and extensively drug-resistant TB and has the potential to allow for injection-free regimens for MDR-TB.

Because of its impressive impact on outcomes, linezolid is likely to become a key component of treatment regimens for drug-resistant TB in sub-Saharan Africa. However, it has never been systematically studied in its populations and there are critical knowledge gaps that need to be addressed prior to the expanded use of this important agent.

To support the scale-up of safer and more effective drug-resistant TB regimens, the study aims to address several knowledge gaps. First, mitochondrial toxicity associated with long-term use of linezolid leads to treatment-limiting adverse events in over a third of patients. It is unclear whether attempts to reduce this by reducing dosage compromise efficacy and facilitate the emergence of linezolid resistance. Second, the risk of toxicity may potentially be different in patients from sub-Saharan Africa because of high rates of HIV co-infection, different population pharmacokinetics, and unique polymorphisms in mitochondrial DNA (mtDNA). Published reports of linezolid use for drug-resistant TB include outcomes data for only 239 patients worldwide; fewer than 10% of these were HIV-infected and only 55 cases have been reported from Africa.

Dr Wasserman and his team will conduct a large prospective pharmacokinetic and pharmacodynamic (PK/PD) study aimed at defining the optimal use of linezolid in South African patients with DR-TB. The specific objectives of the project are to develop a population PK model of linezolid in South African patients with drug-resistant TB; to determine the effects of linezolid exposure on toxicity, treatment response, and linezolid resistance; and to define the relationships between linezolid PK parameters, functional mitochondrial activity, and clinical toxicity, and explore the association of polymorphisms in mtDNA with the risk of linezolid toxicity in this population.

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 study findings will likely inform international guidelines for linezolid use, ultimately translating into improved outcomes for patients with drug-resistant TB.

This project will also enable Dr Wasserman to acquire further skills to lead future clinical and translational studies in the fields of HIV and 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