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EDCTP portfolio: Career Development Fellowships

Dr Clifford George Banda aims to determine the impact of dolutegravir-based ART on the pharmacokinetic profile and placental penetration of piperaquine used in the intermittent preventive treatment of malaria in pregnant women

Pharmacokinetics of piperaquine administered to prevent malaria among pregnant women on standard ART

In malaria-endemic settings in Africa, HIV infection is also highly prevalent and HIV-infected pregnant women are on antiretroviral therapy (ART) and trimethoprim-sulphamethoxazole.

In the case of malaria in pregnancy, dihydroartemisinin-piperaquine (DP) is an effective alternative to sulfadoxine-pyrimethamine (SP) for intermittent preventive treatment of malaria in pregnancy (IPTp) in areas where SP resistance is high. However, it has been shown that the current efavirenz-based ART reduces exposure to piperaquine (the longer-acting partner drug of DP) below purported efficacious concentrations during IPTp. Therefore, different dosing regimens for DP have been suggested and a number of countries with malaria-endemic settings plan to adopt a dolutegravir-based ART regimen for first-line treatment of HIV-infection.

Unfortunately, recently, concerns have arisen regarding possible dolutegravir-associated neural tube defects among children born to women on dolutegravir-based ART (at the time of conception or during the first trimester of pregnancy). This has prompted national HIV programmes to delay the roll-out of dolutegravir in women of childbearing potential and for first-line ART initiation during pregnancy. The challenge is to meet this urgent need to understand their impact on the pharmacokinetic profile and placental penetration of DP.

The challenge

With the PENETRATE study, Dr Banda aims to determine the impact of standard ART on the pharmacokinetic profile and placental penetration of piperaquine administered as DP for intermittent preventive treatment of malaria in pregnant women in Malawi.

A pharmacokinetic cohort study – nested within two large on-going EDCTP-MRC funded clinical trials (IMPROVE I & II) – will be conducted in two steps among HIV-uninfected and matched HIV-infected pregnant women who started dolutegravir-based ART.

First, plasma blood samples will be collected over a period of 28 days following intake of DP to compare pharmacokinetic (PK) parameters of piperaquine between the HIV-infected and HIV-uninfected groups.

Secondly, two similar separate cohorts of women from the IMPROVE trials will have a paired maternal plasma and umbilical cord vein sample collected at delivery to compare the ratio of maternal/umbilical cord piperaquine concentrations between HIV-uninfected and HIV-infected pregnant women on standard ART.

The project

Findings of the PENETRATE study will inform accurate dosing of DP when co-administered with standard ART, thereby informing the dosing regimen of dihydroartemisinin-piperaquine in the IMPROVE II clinical trial and contributing to the pool of evidence needed by WHO to recommend the use of DP for IPTp among HIV-uninfected and -infected pregnant women on standard ART 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

In malaria-endemic settings in Africa, HIV infection is also highly prevalent and HIV-infected pregnant women are on antiretroviral therapy (ART) and trimethoprim-sulphamethoxazole.

In the case of malaria in pregnancy, dihydroartemisinin-piperaquine (DP) is an effective alternative to sulfadoxine-pyrimethamine (SP) for intermittent preventive treatment of malaria in pregnancy (IPTp) in areas where SP resistance is high. However, it has been shown that the current efavirenz-based ART reduces exposure to piperaquine (the longer-acting partner drug of DP) below purported efficacious concentrations during IPTp. Therefore, different dosing regimens for DP have been suggested and a number of countries with malaria-endemic settings plan to adopt a dolutegravir-based ART regimen for first-line treatment of HIV-infection.

Unfortunately, recently, concerns have arisen regarding possible dolutegravir-associated neural tube defects among children born to women on dolutegravir-based ART (at the time of conception or during the first trimester of pregnancy). This has prompted national HIV programmes to delay the roll-out of dolutegravir in women of childbearing potential and for first-line ART initiation during pregnancy. The challenge is to meet this urgent need to understand their impact on the pharmacokinetic profile and placental penetration of DP.

With the PENETRATE study, Dr Banda aims to determine the impact of standard ART on the pharmacokinetic profile and placental penetration of piperaquine administered as DP for intermittent preventive treatment of malaria in pregnant women in Malawi.

A pharmacokinetic cohort study – nested within two large on-going EDCTP-MRC funded clinical trials (IMPROVE I & II) – will be conducted in two steps among HIV-uninfected and matched HIV-infected pregnant women who started dolutegravir-based ART.

First, plasma blood samples will be collected over a period of 28 days following intake of DP to compare pharmacokinetic (PK) parameters of piperaquine between the HIV-infected and HIV-uninfected groups.

Secondly, two similar separate cohorts of women from the IMPROVE trials will have a paired maternal plasma and umbilical cord vein sample collected at delivery to compare the ratio of maternal/umbilical cord piperaquine concentrations between HIV-uninfected and HIV-infected pregnant women on standard ART.

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.

Findings of the PENETRATE study will inform accurate dosing of DP when co-administered with standard ART, thereby informing the dosing regimen of dihydroartemisinin-piperaquine in the IMPROVE II clinical trial and contributing to the pool of evidence needed by WHO to recommend the use of DP for IPTp among HIV-uninfected and -infected pregnant women on standard ART 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