“
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.

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