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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

Tenofovir disoproxil fumarate (TDF) is the most widely used antiretroviral drug (ART) due to its antiviral potency, safety profile and tolerability. However, TDF causes proximal tubular renal dysfunction (PTRD) leading to Fanconi syndrome, acute kidney injury and chronic kidney damage.

The challenge is to get better data on the association of TDF and PTRD in African HIV patients.

Dr Karoney is conducting the TREND study, a cross-sectional analytic study of HIV-infected patients attending the Academic Model Providing Access to Healthcare programme in Western Kenya. Laboratory tests will be carried out to determine the outcomes of interest.

The primary outcome for this study is PTRD while the secondary outcome is estimated glomerular filtration rate (GFR). TDF-induced renal toxicity can be missed because it is initially subclinical and manifests as PTRD. Studies investigating TDF toxicity using estimated GFR report only 2-4% prevalence while studies investigating PTRD report up to 22% prevalence. PTRD is determined through urinalysis for glucose and tubular proteinuria, serum phosphate, and bone fracture rate.

The TREND study will compare PTRD among HIV-infected patients on a TDF regimen and patients on TDF-sparing regimen and compare the estimated GFR among HIV-infected patients on TDF regimen and patients on TDF sparing regimen. This study will also assess the determinants of the association between PTRD and TDF use in HIV-infected patients and determine the sensitivity and specificity of normoglycemic glucosuria in assessing proximal tubular renal dysfunction in HIV patients on 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.

There is limited data on TDF-induced PTRD among African patients and lack of proper guidelines on lab monitoring. This study will add new knowledge on subclinical tubular injury and improve monitoring guidelines as well as validate the use of simpler markers for detection of PTRD.

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