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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

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