Dr Mercy Karoney

Kenya

EDCTP portfolio: Career Development Fellowships

Dr Mercy Karoney conducts a study to acquire better data on proximal tubular renal dysfunction in African HIV-patients on ART.

Proximal tubular renal dysfunction among HIV patients on tenofovir versus tenofovir-sparing regimens

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.

The challenge

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

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.

Impact


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

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

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

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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