Publications

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

Dr Richard Mwaiswelo

Tanzania

EDCTP portfolio: Career Development Fellowships

Dr Richard Mwaiswelo assesses the safety and efficacy of low-dose primaquine for P. falciparum gametocyte clearance and transmission blocking in patients with reduced or null CYP2D6 activity.

Assessing the safety of primaquine added to standard malaria treatment

The World Health Organization (WHO) has now recommended the addition of a 0.25 mg/kg single-dose primaquine (PQ) to standard artemisinin-based combination therapy for the elimination of Plasmodium falciparum malaria in low-transmission settings and for containment in areas threatened by artemisinin resistance. The dose has shown to be safe even in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency and is efficacious for clearance of P. falciparum gametocytes. However, due to remaining safety concerns, most malaria-endemic sub-Saharan African countries have not adopted the PQ recommendation.

Some individuals with normal G6PD status nonetheless developed adverse events, including acute hemolysis following treatment with this single low-dose PQ. Furthermore, a failure rate of =5 has also been reported in gametocyte clearance and transmission-blocking after treatment with even high doses of PQ, which suggests other factors being involved in determining PQ safety and efficacy. This study aims to collect better information regarding the effect of CYP2D6 isoenzyme polymorphism on PQ safety and its efficacy in sterilizing mature P. falciparum gametocytes.

The challenge

Dr Mwaiswelo and his team aim to assess the safety and efficacy of 0.25 mg/kg single-dose PQ when added to standard artemether-lumefantrine regimen for clearance and blocking transmission of P. falciparum gametocytes in patients with CYP2D6 reduced/null activity as compared to those with normal/increased enzyme activity.

Children 1-10 years of age and with uncomplicated P. falciparum malaria will be enrolled (155) and treated with standard artemether-lumefantrine regimen plus a 0.25 mg/kg single-dose of PQ and then followed up on days 0, 1, 2, 3, 7, 14, 21 and 28 for clinical and laboratory assessment. Primaquine is administered with the first dose of artemether-lumefantrine. Safety assessment is performed using the PQ Roll-Out Monitoring Pharmacovigilance Tool.

Gametocytes are being detected and quantified by microscopy and Pfs25 mRNA quantitative nucleic acid sequence-based amplification (QT-NASBA) on days 0 and 7. For a subset of 100 participants, post-treatment infectiousness will be assessed by mosquito feeding assays on day 7. The CYP2D6 status will be determined using PCR followed by restriction fragment length polymorphism (RFLP) analyses.

The project

The expected impact will be to establish the much-needed information on the safety and efficacy of 0.25 mg/kg single-dose PQ in individuals with reduced/null compared to those with normal/increased CYP450 2D6 isoenzyme activity. This information is needed before the WHO PQ policy can be implemented, especially in sub-Saharan Africa.

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 World Health Organization (WHO) has now recommended the addition of a 0.25 mg/kg single-dose primaquine (PQ) to standard artemisinin-based combination therapy for the elimination of Plasmodium falciparum malaria in low-transmission settings and for containment in areas threatened by artemisinin resistance. The dose has shown to be safe even in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency and is efficacious for clearance of P. falciparum gametocytes. However, due to remaining safety concerns, most malaria-endemic sub-Saharan African countries have not adopted the PQ recommendation.

Some individuals with normal G6PD status nonetheless developed adverse events, including acute hemolysis following treatment with this single low-dose PQ. Furthermore, a failure rate of =5 has also been reported in gametocyte clearance and transmission-blocking after treatment with even high doses of PQ, which suggests other factors being involved in determining PQ safety and efficacy. This study aims to collect better information regarding the effect of CYP2D6 isoenzyme polymorphism on PQ safety and its efficacy in sterilizing mature P. falciparum gametocytes.

Dr Mwaiswelo and his team aim to assess the safety and efficacy of 0.25 mg/kg single-dose PQ when added to standard artemether-lumefantrine regimen for clearance and blocking transmission of P. falciparum gametocytes in patients with CYP2D6 reduced/null activity as compared to those with normal/increased enzyme activity.

Children 1-10 years of age and with uncomplicated P. falciparum malaria will be enrolled (155) and treated with standard artemether-lumefantrine regimen plus a 0.25 mg/kg single-dose of PQ and then followed up on days 0, 1, 2, 3, 7, 14, 21 and 28 for clinical and laboratory assessment. Primaquine is administered with the first dose of artemether-lumefantrine. Safety assessment is performed using the PQ Roll-Out Monitoring Pharmacovigilance Tool.

Gametocytes are being detected and quantified by microscopy and Pfs25 mRNA quantitative nucleic acid sequence-based amplification (QT-NASBA) on days 0 and 7. For a subset of 100 participants, post-treatment infectiousness will be assessed by mosquito feeding assays on day 7. The CYP2D6 status will be determined using PCR followed by restriction fragment length polymorphism (RFLP) analyses.

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 expected impact will be to establish the much-needed information on the safety and efficacy of 0.25 mg/kg single-dose PQ in individuals with reduced/null compared to those with normal/increased CYP450 2D6 isoenzyme activity. This information is needed before the WHO PQ policy can be implemented, especially in sub-Saharan Africa.

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