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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

There is no vaccine which protects against infection or pulmonary tuberculosis (TB) and TB therapeutics require a cumbersome lengthy (6 months) regimen in the case of drug-susceptible Mycobacterium tuberculosis (Mtb). This often leads to poor compliance or discontinued treatment, which also facilitates the development of antibiotic resistance.

An innovative treatment approach (host-directed therapy) focuses on host processes to shorten treatment without inducing drug-resistance. In this case, the project sets as its goal to determine the effect of sildenafil on Mtb survival in myeloid-derived suppressor cells.

Myeloid-derived suppressor cells (MDSCs) accumulate during inflammatory conditions to suppress host immunity to limit tissue pathology. We and others showed that MDSCs represent a critical element in the pathogenesis of pulmonary TB. MDSCs increase during TB disease, contain Mtb bacilli, suppress protective host immunity and modulate lung inflammation.

Recently, PDE-5 inhibition was tested in mouse tumour models and shown to reverse tumour-induced immunosuppression and induce antitumor immunity that delayed tumour progression. Subsequently, PDE-5 inhibitors (including sildenafil/Viagra^®) are being repurposed, tested in human clinical trials for the treatment of malignancies. In particular, sildenafil has shown to improve cancer therapy by up-regulating T-cell numbers in tumours, increase T-cell activation and T-cell IL-2 production. Importantly, sildenafil mediated this improved response by dampening MDSC recruitment and down-regulating MDSCs-derived T-cell suppression. Reports show that the therapeutic treatment of Mtb-infected mice with sildenafil accelerated lung sterilisation when added to the standard TB-treatment regimen, but the mechanism of action remains unknown.

The role of sildenafil on human MDSCs in the context of TB has not been evaluated and further groundwork is needed to better understand how PDE-5 inhibitors might be beneficial in combination with standard TB-treatment. Dr Du Plessis and her team hypothesise that delivery of sildenafil to MDSC from TB patients could alter MDSCs phenotype and function. They will test this in two ways by 1) evaluating the immune-modulatory capacity of sildenafil on the function and phenotype of MDSC from lungs and blood of TB patients, and 2) determining the effect of sildenafil on Mtb survival in MDSCs.

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.

The immediate impact will be to further Dr Du Plessis career development by facilitating increased scientific output (peer-reviewed publications), increased student training, broadening her local and international network and establishing her myself as a leader in the field of MDSCs research in TB.

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