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test the safety and efficacy of this new formulation in young children

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Bringing antiretroviral drugs to children

The CHAPAS trials have ensured that many more children with HIV have benefited
from life-saving antiretrovirals.

The challenge

Despite the high prevalence of HIV in sub-Saharan Africa, cardiovascular diseases (CVD) are the leading causes of morbidity and mortality in this region. Predictors of CVD are well established in resource-rich countries, but whether these same risk factors are strongly associated with CVD in sub-Saharan Africa is not known. Growing evidence from Europe suggests that HIV itself may be a risk factor for CVD. The challenge is to establish whether HIV infection contributes to the risk of early CVD in sub-Saharan Africa. As it remains unclear whether inflammation and immune activation truly predict the early risk of CVD in African HIV-infected subjects.

Dr Temu and her team hypothesise that systemic immune activation and inflammation associated with HIV infection contribute to the early risk of CVD in HIV-positive individuals and that Cytomegalovirus (CMV) infection and microbial translocation may contribute to this process.

Therefore, she aims to determine if HIV-infected individuals have increased inflammation and immune activation compared to the uninfected controls, and is testing whether the markers of immune activation and inflammation are associated with an increased risk of subclinical atherosclerosis.

The study is a cross-sectional, case-control study of 200 HIV-positive and 100 HIV-negative subjects nested in the ongoing Kenya study of cardiovascular diseases during HIV infection with a cohort of 300 HIV-infected on long-term antiretroviral treatment and 300 HIV-uninfected subjects. Dr Temu’s study analyses banked blood from the study for markers of inflammation, CMV infection, microbial translocation and cellular immune activation, selected for their association with CVDs in HIV-uninfected populations. Associations with subclinical atherosclerosis in HIV-positive patients (adjusting for age, sex, HIV-related and traditional risk factors) are also investigated. A set of candidate biomarkers may be derived for prospective validation.

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.

This innovative and important clinical study on a well-characterised cohort will illuminate the mechanisms leading to increased risk of CVD in HIV-infected individuals and provide data that will be critical to developing targeted, feasible intervention trials to combat CVD in sub-Saharan Africa over the next decade.

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