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Clinical research, drug efficacy & resistance

By Colin Sutherland

Malaria Centre researchers are making a concerted contribution to improving two key aspects of malaria case management – diagnosis and chemotherapy. Detection of parasites remains the essential step in confirming a patient has malaria but this can be particularly challenging in low transmission and near-elimination areas where the majority of fever presentations are not caused by malaria. Once identified, effective treatment requires that malaria drugs are of good quality, and our work has pioneered methods for ensuring that substandard, degraded or falsified malaria medicines are identified and tracked. Finally, treatment will not be fully effective if the patient harbours resistant malaria parasites, and we are recognised as world leaders in identifying antimalarial drug resistance in the lab, and monitoring treatment failure in the field.

The appropriate treatment of malaria in endemic countries can be hindered by several factors. Malaria patients with G6PD deficiency are unable to tolerate drugs of the 8-aminoquinoline class, which includes primaquine and tafenoquine, particularly important for preventing Plasmodium vivax relapses. Malaria Centre members are leading the development and implementation of a highthroughput standardisable platform for identifying patients with G6PD deficiency, who are at much greater risk of post-treatment haemolytic anaemia when 8-aminoquinolines are used, so that alternative regimens can be deployed. The platform also enables identification of other haemoglobinopathies such as HbC and HbS.

One drug now being more heavily used across the malaria endemic world is piperaquine, which is associated with a level of cardiac toxicity. Piperaquine is now being considered (in a combination) for prophylactic treatment to protect pregnant women from P. falciparum, and the Malaria Centre is leading a study in northern Tanzania, where other options are precluded by the presence of resistant parasites, to evaluate the safety of regular piperaquine use in this important at-risk group. Drug resistance emerging in SE Asia, associated with mutations in the gene for the K13 propeller protein that enable a proportion of ring stage parasites to survive artemisinin, is of concern, but the few documented treatment failures in African parasites do not bear this genetic signature.

In Indonesian studies of ACT efficacy, we also find no evidence of artemisinin resistance, although the complexity of multi-species infections makes efficacy studies more difficult to carry out. New work in the Malaria Centre has been investigating two candidate genes, pfubp1 and pfap2mu, originally identified in artemisinin-resistant rodent malaria parasites, and demonstrated that mutations introduced by CRISPR do indeed generate a ring-stage resistance phenotype in vitro. Further, and exploration of the cellular functions of the AP2-m protein in P. falciparum has provided clear evidence that its role in the parasite is distinct from its normal endocytic trafficking role in other eukaryotic cells.

Drug quality is also key to successful management of malaria, and the Malaria Centre team have been conducting surveillance in Equatorial Guinea to monitor this potential problem. 91% of artemisinin-based therapies were found to be of acceptable quality, but the majority of the remainder were falsified. These data are vital for international efforts to curtail the criminal activity leading to sale of these products in malaria endemic areas.

Finally, the Malaria Centre is also involved in projects combining antimalarial therapy with other interventions. In Mali and Burkina Faso we are working with our local collaborators to investigate the impact of combining seasonal malaria chemoprevention in children under 5 with vaccination, using the RTS,S vaccine recently licensed for use in Africa. We have also been evaluating the utility of combining seasonal malaria chemoprevention with monthly azithromycin (a broad spectrum antibiotic) in preventing childhood mortality. Whereas this provided some benefit in lowering the incidence of non-malaria fevers, there was no measurable benefit in reducing mortality in the target group.