Using evidence to guide best practice

Prof Azra C Ghani, Imperial College London, UK & Prof Fred Binka, Principal Investigator of INESS

Artemisinin-based combination therapies (ACTs) are today’s gold standard antimalarials. Eurartesim® (dihydroartemisinin-pip-eraquine) and Pyramax® (pyronaridine- artesunate) are the latest ACTs to emerge from MMV’s pipeline.

These two new medicines add to the choice of antimalarials, enabling disease-endemic countries to adapt control strategies to their specific needs. Mathematical modelling studies suggest that using multiple first-line ACTs could yield better clinical outcomes than deploying a single ACT nationwide particularly when drug resistance or treatment failures emerge.1,2 The key now is to gather the evidence to guide optimal and widespread use of new ACTs like Eurartesim and Pyramax.

A medicine’s performance in routine practice can differ from its performance in carefully controlled clinical trials. Trials recruit thousands of patients who, due to strict inclusion criteria, do not always reflect the physiological profiles of the ultimate treatment population. To help guide best treatment practice in differing populations, it is important to continue to gather evidence post-approval.

Theoretical assumptions can initially be made using mathematical models. Models and malaria have gone hand-in-hand since the early 20th century, when Sir Ronald Ross pioneered their use for infectious diseases. They were later explored to help develop the first eradication strategy in the 1950s.

Prof Azra C Ghani, Imperial College London, UK, explains how these models are being used today.

1. How are mathematical models helping to inform National Malaria Control Programmes about the tools best suited to their countries?

To date, they have mostly been used in a malaria research context and to advise at a global level, but their use is growing. There is increasing interest from National Malaria Control Programmes in using models, especially as they see budgets being cut and need to devise cost-effective strategies using available interventions: bednets, indoor spraying, chemoprophylaxis or a vaccine when it comes. A combination of models and health economics can guide rational use of these interventions in different settings.

2. What can the models tell us about the use of medicines in blocking transmission?

There are two key properties of an antimalarial: first, how quickly it clears parasites – treating the patient and preventing transmission – and second, how long the drug remains in the body, protecting it from further infection – an issue that is very important in high-transmission settings. In these settings, a drug like Eurartesim would be useful owing to its long half-life. In a low-transmission setting, however, just a few infections sustain transmission so the key is to cure them quickly and eliminate the reservoir. This suggests a ‘one drug fits all’ approach is not the best, and gives an indication of the kind of drugs that would be more appropriate in different settings. Ideally, we need a drug with fast gametocytocidal action to prevent transmission and long activity to provide post-treatment protection.

Theory aside, we need to understand the reality through trials in real-life settings, such as INESS.3 In addition, with the support of the European & Developing Countries Clinical Trials Partnership (EDCTP) led by Prof. Charles Mgone, MMV is working with the West African Network for Clinical Trials of Antimalarial Drugs (WANECAM) to conduct some longitudinal studies of Eurartesim and Pyramax. This research is particularly important for Pyramaxas elevations in liver enzymes were noted in a small number of subjects following treatment with the medicine. Repeat dose findings to date are reassuring (no differences in the liver enzymes between first and subsequent dosing) and have enabled children as young as 6 months to be included in the study.

Prof. Fred Binka, Principal Investigator of INESS explains how it will gather data on the safety and effectiveness of these new ACTs.

1. How is INESS helping to gather evidence to improve malaria treatment?

Using census data collected in Ghana, Burkina Faso, Mozambique and Tanzania as a baseline, we gather information on malaria patients directly from healthcare facilities. We look at how easy it is to access health care, how long it takes to get treatment, which treatment they receive and their compliance to the regimen. We then follow-up in their homes to see if there are any adverse reactions. What we are really looking at is not the effectiveness of the drug alone, but the effectiveness of the system to deliver the drugs as well, to find out where the pitfalls lie.

2. What has the study revealed so far? What do you expect to discover in terms of the different attributes of available ACTs?

So far, we have looked at two ACTs: artemether-lumefantrine (AL) and artesunate-amodiaquine (AS-AQ). The differences we have seen in terms of effectiveness tend to reflect differences in health systems rather than in the drugs. When we start to look at Eurartesim, as an ACT that provides longer post-treatment prophylaxis, we might start to see differences. It will be interesting to see what these are.

1. Boni MF, Smith DL, Laxminarayan R. “Benefits of using multiple first-line therapies against malaria.” Proc Natl Acad Sci USA. 105(37):14216-21 (2008).

2. Smith DL et al. “Prospective strategies to delay the evolution of anti-malarial drug resistance: weighing the uncertainty.” Malar J. 9:217 (2010)

3. INESS: INDEPTH Effectiveness and Safety Studies of Anti-malarial Drugs in Africa