Dr Aida Sivro

South Africa

EDCTP portfolio: Career Development Fellowships

Dr Aida Sivro aims to disentangle the mechanisms that govern the positive and negative effects of host interferon on HIV susceptibility.

Mucosal type I IFN desensitisation and the risk of HIV acquisition

Host interferon (IFN) antiviral response is an important determinant of HIV transmission during sexual exposure. Recent data from animal models suggest that mucosal application of type I IFNs can block viral infection and might represent an HIV prevention strategy.

However, in a prospective cohort analysis of the CAPRISA 004 trial increased mucosal type I IFN expression was associated with an increased risk to acquire HIV. One of the explanations for this discrepancy could be the timing and duration of IFN exposure. In the animal model, exogenous IFN exposure was brief, whereas, in humans, endogenous IFN expression can be maintained at high levels for a prolonged period of time. The challenge is to disentangle the mechanisms that govern the positive and negative effects of IFN on HIV susceptibility.

The challenge

Dr Sivro hypothesises that chronic type I IFN expression in the female reproductive tract causes dysregulation of IFN responsiveness, therefore increasing the susceptibility of HIV target cells in the mucosa. She and her team will measure patterns of type I IFN expression longitudinally at the female reproductive tract. Type I IFN levels will be plotted over time and cumulative IFN score will be calculated. Participants with persistently high and low type I IFN levels will be identified. Type I IFN levels will then be correlated to demographic, clinical, behavioural and reproductive variables. Finally, they will correlate the high/low IFN status with IFN responsiveness and altered HIV susceptibility of mucosal target cells.

The project

This study aims to contribute to an understanding of how basic immunological mechanisms are exploited by HIV. Resolving the controversy around IFNs and HIV transmission is critical if IFN therapies are going to be considered for clinical translation. The Centre for the AIDS Programme of Research in South Africa (CAPRISA) is one of South Africa’s best-known research organisations and will provide the fellow with the necessary support and international research environment to further her development as an independent researcher. Furthermore, through this fellowship Dr Sivro will supervise students from the University of KwaZulu- Natal, transferring her skills and knowledge to a new generation of researchers in South Africa.

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

Host interferon (IFN) antiviral response is an important determinant of HIV transmission during sexual exposure. Recent data from animal models suggest that mucosal application of type I IFNs can block viral infection and might represent an HIV prevention strategy.

However, in a prospective cohort analysis of the CAPRISA 004 trial increased mucosal type I IFN expression was associated with an increased risk to acquire HIV. One of the explanations for this discrepancy could be the timing and duration of IFN exposure. In the animal model, exogenous IFN exposure was brief, whereas, in humans, endogenous IFN expression can be maintained at high levels for a prolonged period of time. The challenge is to disentangle the mechanisms that govern the positive and negative effects of IFN on HIV susceptibility.

Dr Sivro hypothesises that chronic type I IFN expression in the female reproductive tract causes dysregulation of IFN responsiveness, therefore increasing the susceptibility of HIV target cells in the mucosa. She and her team will measure patterns of type I IFN expression longitudinally at the female reproductive tract. Type I IFN levels will be plotted over time and cumulative IFN score will be calculated. Participants with persistently high and low type I IFN levels will be identified. Type I IFN levels will then be correlated to demographic, clinical, behavioural and reproductive variables. Finally, they will correlate the high/low IFN status with IFN responsiveness and altered HIV susceptibility of mucosal target cells.

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 study aims to contribute to an understanding of how basic immunological mechanisms are exploited by HIV. Resolving the controversy around IFNs and HIV transmission is critical if IFN therapies are going to be considered for clinical translation. The Centre for the AIDS Programme of Research in South Africa (CAPRISA) is one of South Africa’s best-known research organisations and will provide the fellow with the necessary support and international research environment to further her development as an independent researcher. Furthermore, through this fellowship Dr Sivro will supervise students from the University of KwaZulu- Natal, transferring her skills and knowledge to a new generation of researchers in South Africa.

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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