EDCTP portfolio: Career Development Fellowships

Dr Mosepele Mosepele aims to address the knowledge gap regarding albuminuria with inflammation (and its reduction) as a factor in the long-term health of African HIV-infected patients.

Albuminuria and the long-term health of HIV-patients

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.

The challenge

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

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.

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

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

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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