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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

HIV infection is associated with a five-fold risk of albuminuria. Albuminuria causes HIV-infected patients up to four times more likely to die. It is well known from Western populations that persistent albuminuria with inflammation is a marker of excess end-organ dysfunction and mortality among HIV-infected adults with undetectable HIV-1 RNA (viral load suppression on antiretroviral treatment or ART).

As more HIV-infected patients attain viral suppression and prolonged survival globally, they are faced with multiple non-communicable diseases mostly characterised by accelerated end-organ dysfunction which threatens their long-term health and longevity. It is believed that persistent inflammation despite viral suppression drives most of the observed end-organ dysfunction. Studies involving HIV-infected and HIV-uninfected persons outside Africa have shown albuminuria to be a marker of end-organ dysfunction (e.g. cardiovascular disease, renal dysfunction, and even cognitive impairment), and demonstrate that albuminuria is highly correlated with inflammation.

However, the burden of albuminuria with inflammation has not been well characterised among black African patients. In addition, although angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARBs) are widely available, their role in reducing albuminuria with inflammation in African HIV-infected patients has not been studied.

Dr Mosepele proposed a prospective observational non-interventional study to determine the prevalence and longitudinal changes in albuminuria in a clinical setting with high rates of viral suppression. He will also assess if longitudinal changes in albuminuria are associated with ACEI/ARB exposure over a 12-month period in a clinical setting. The association between longitudinal changes in albuminuria and inflammatory markers and whether this association is affected by the use of ACEI/ARB will also be assessed. Finally, dr Mosepele plans to enrol a cohort to assess long-term HIV-Cardiovascular Disease outcomes. Biospecimens will be stored for future testing of other inflammation markers as well as data on host genetics (e.g., APOL-1 allele variant frequency). Five-year mortality in the death registry will be linked to longitudinal changes in albuminuria.

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.

Results of this study will provide baseline data to inform the design of a clinical trial to assess whether HIV disease is a compelling indication for early ACEI/ARB prescription among hypertensive HIV-infected patients given the positive pleiotropic effects of these medications on albuminuria, inflammation and cardiac remodelling. As the fellow plans to lead such a study, the current fellowship may facilitate further career development.

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