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We talk to Prabin Dahal, a DPhil student in WWARN, the WorldWide Antimalarial Resistance Network based in the Centre for Tropical Medicine and Global Health. WWARN is a global collaboration of malaria researchers working to ensure that anyone affected by malaria receives effective and safe drug treatment.

Extracted from Issue 26, October 2015 OxfordMedSci News.

Tell us a little about the work in your group

Prabin DahalAt WWARN, we actively collect and collate individual patient data from studies to provide reliable evidence on the factors affecting the efficacy of antimalarial medicines.

In my group, I am using a statistical technique called meta-analysis to amalgamate and review previous research. We use meta-analyses to investigate factors associated with poor treatment outcomes for patients treated with artemisinin based combination therapies (ACTs), the most widely used malaria treatments. There are several challenges associated with this. For instance, the individual studies will often have used different trial protocols, study populations or laboratory techniques, making it difficult to compare the data. We standardise the data first so that all the trials can be analysed using a common protocol; this enables us to look at the data as a whole so that we can answer questions of public health importance.

What are the implications of your research?

WWARN screenshotSuch pooled analyses help us to identify and understand the patient populations who are vulnerable to poor treatment outcomes. This is only feasible through WWARN’s approach of using individual patient data meta-analysis, as any single study lacks the statistical power to examine the different risk factors associated with treatment outcomes – the strength of our research is in numbers! For example, in a recently published pooled analysis, we identified that children who were underweight had a lower exposure to drugs compared to those who were adequately nourished and hence were at a high risk of poor therapeutic outcomes (WWARN AL Study Group, WWARN AL PK Study group). This suggests that more frequent or prolonged dosage regimens should now be evaluated in very young malnourished children, while carefully monitoring the toxicity associated with increased dose.

Slow parasite clearance is a key clinical manifestation of reduced susceptibility to artemisinin. Another recently published study (WWARN Africa Baseline Study Group) was designed to establish the baseline values for parasite clearance in patients from Sub-Saharan African countries treated with ACTs. The current threshold for potential artemisinin resistance has been proposed as a positivity rate three days after treatment of greater than 10%. This threshold was derived mainly from data from trials in Asia. However, our meta-analysis clearly shows that the baseline prevalence of positivity is much lower in African patients and hence provides much-needed evidence that a ‘one-size-fits-all’ threshold should be employed with caution. We concluded that thresholds tailored to specific populations (e.g. 5% in Africa) will be much more sensitive as an early warning signal.

From a public health point of view, our work is very important as this provides much-needed information for effective case management and optimal patient care. It also provides evidence for the policy makers for formulating guidelines. For example, our very first pooled analysis (WWARN DP study group) had a translational research impact. It provided critical information regarding the dose-response relationship which led to revised dosing recommendations by the WHO for the treatment of children (WHO 2015). 

How many people are there in your group? And, from what backgrounds?

We are about 15 people in Oxford, with around 20 people who are based overseas. We currently work with 257 collaborating partners across the world. The Oxford team is a vibrant mix of informatics, biologists, clinicians, communication managers, pharmacologists, microscopists, mathematicians and statisticians. Our collaboration is cross-cutting, bringing together clinical, biological, pharmacological and mathematical expertise to better understand the disease and treatment. This is what makes WWARN such a great place to work as we feed into each other’s work and gain from it.

How did you get to where you are today?

I spent a year at GlaxoSmithKline (GSK) as an undergraduate through a placement scheme in the pharmaceutical development and safety assessment group. My work involved assessing the dose-related safety and toxicity of novel compounds, and exploring optimal operational conditions for manufacturing drug tablets. I really enjoyed what I was doing at GSK and this motivated me to study for an MSc in Biometry at the University of Reading. The course focused on the application of statistics to medical and biological sciences. This led me to the role of medical statistician at Oxford. Now, I am currently pursuing a DPhil in clinical medicine, tackling methodological issues in quantification of drug efficacy.

What’s a typical day at work like for you?

It is quite varied as I’m concurrently working on many projects. It involves conducting data analysis, performing literature reviews and keeping myself updated with current literature in malaria and statistics, drafting the results of analysis for presentations and publications, attending seminars and so on. I also get occasional requests from journals for peer-reviews.

What are the bigger questions in your field? How do you see your field developing in the next ten years?

The emergence of resistance to the most potent class of antimalarial drugs (ACTs) in Southeast Asia is a huge concern. In the past, malaria parasites that are resistant to antimalarial treatments have spread from Southeast Asia into India and the African sub-continent. The spread of resistance to Africa would be disastrous and undo all the remarkable progress achieved in the last decade. If this happens, patients will be without any effective treatment as the current drug arsenal for combating malaria is very limited. In the next ten years, hopefully there will be new drugs for treatment, an effective vaccine and a much more concentrated global effort towards the elimination of malaria.

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