The VirTUAL study is combining modelling and clinical research to identify the optimal drug treatments for pregnant women, children and adolescents with HIV and TB.

Treating TB and HIV in neglected groups

As more people gain access to antiretroviral therapy, new challenges are arising in the management of HIV, and more tailored approaches to treatment are required.

For example, every year around one in ten people being treated for HIV transfer to second-line antiretroviral therapy, because of drug resistance or other factors. Second-line therapy includes drugs known as boosted protease inhibitors, which interact with a key anti-TB drug, rifampicin. Determining the most appropriate dose of boosted protease inhibitors is therefore challenging, particularly in groups such as pregnant women, children and adolescents who are generally excluded from clinical trials.

The challenge

The VirTUAL project is drawing on existing data, conducting new clinical studies and using modelling to determine and test the most appropriate dosing of boosted protease inhibitors in second-line treatment of HIV.

It will use an approach known as physiologically based pharmacokinetic modelling to explore how rifampicin affects the metabolism and excretion of boosted protease inhibitors and their distribution around the body. These analyses will reveal the drug doses likely to be necessary for antiretroviral concentrations to be high enough to effectively suppress HIV replication.

The results of the modelling will be tested in clinical pharmacokinetic studies, with gradually increasing levels of boosted protease inhibitors being given to patients receiving high-dose rifampicin. Pharmacokinetic modelling will also be used to determine appropriate antiretroviral doses for special populations, such as pregnant women, children and adolescents.

The project

The VirTUAL project will provide much-needed data on complex but increasingly common clinical scenarios in HIV management, including antiretroviral use in vulnerable and neglected populations. In addition, it will build the capacity of African scientists in pharmacokinetic modelling, increasingly used to identify dosing strategies for evaluation in clinical trials.

Impact


crucial in

widening African

children’s access

to antiretrovirals

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

As more people gain access to antiretroviral therapy, new challenges are arising in the management of HIV, and more tailored approaches to treatment are required.

For example, every year around one in ten people being treated for HIV transfer to second-line antiretroviral therapy, because of drug resistance or other factors. Second-line therapy includes drugs known as boosted protease inhibitors, which interact with a key anti-TB drug, rifampicin. Determining the most appropriate dose of boosted protease inhibitors is therefore challenging, particularly in groups such as pregnant women, children and adolescents who are generally excluded from clinical trials.

The VirTUAL project is drawing on existing data, conducting new clinical studies and using modelling to determine and test the most appropriate dosing of boosted protease inhibitors in second-line treatment of HIV.

It will use an approach known as physiologically based pharmacokinetic modelling to explore how rifampicin affects the metabolism and excretion of boosted protease inhibitors and their distribution around the body. These analyses will reveal the drug doses likely to be necessary for antiretroviral concentrations to be high enough to effectively suppress HIV replication.

The results of the modelling will be tested in clinical pharmacokinetic studies, with gradually increasing levels of boosted protease inhibitors being given to patients receiving high-dose rifampicin. Pharmacokinetic modelling will also be used to determine appropriate antiretroviral doses for special populations, such as pregnant women, children and adolescents.

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 VirTUAL project will provide much-needed data on complex but increasingly common clinical scenarios in HIV management, including antiretroviral use in vulnerable and neglected populations. In addition, it will build the capacity of African scientists in pharmacokinetic modelling, increasingly used to identify dosing strategies for evaluation in clinical trials.

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

About us

The European & Developing Countries Clinical Trials Partnership (EDCTP) is a public–public partnership between 14 European and 16 African countries, supported by the European Union. EDCTP’s vision is to reduce the individual, social and economic burden of poverty-related infectious diseases by affecting sub-Saharan Africa. EDCTP’s mission is to accelerate the development of new or improved medicinal products for the identification, treatment and prevention of infectious diseases, including emerging and re-emerging diseases, through pre- and postregistration clinical studies, with emphasis on phase II and III clinical trials. Our approach integrates conduct of research with development of African clinical research capacity and networking. The second EDCTP programme is implemented by the EDCTP Association supported under Horizon 2020, the European Union’s Framework Programme for Research and Innovation.

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