Professor Nick White, one of the world’s foremost experts in treating malaria, just published a fantastic review (Malaria Journal – open access!) on the topic. The article presents a great discussion of  measurement issues and common limitations, analyzing by density reduction or time until clearance, the kinetics and trend of results, connections with stage-specific action, and much more. As we’re in the midst of analyzing two years of artesunate+sulphadoxine-pyrimethamine trial data from India’s National Antimalarial Therapeutic Efficacy Monitoring Network, we’re fortunate for the release of the article since examining the parasite clearance in our patients is one of the key concerns.

Viewing the tabulated data for any study (as opposed to just summary data) is a bit tricky: > click on the study icon on the map > look to the bottom left of the pop-up > click investigate study and a new pop-up will appear.

While there are few (clinical) studies in the database thus far, WWARN should be commended for the extent of raw data they make available for each, including:

• Location map
• Study profile
• Patient age range
• Recurrent parasitemias
• WHO treatment outcomes
• PCR-Adjusted cure-rate chart
• Unadjusted cure-rate chart
• Cure-rate table

For the first claim no citation, efficacy or parasite clearance time data, or evidence of any sort are mentioned including who these researchers might be. The (presented) basis for the second claim lies in the screening of just 2,782 persons (it is unclear if this was a mass survey or several months of active case detection) in which only 2 P. falciparum cases were found. I realize this is not a scientific paper, but the ‘screening’ of a few thousand people in a border population of millions before the main malaria transmission season over the upcoming months seems little to be excited about. What was the need for this? The project just began in 2009. Why not wait another two years before making any public pronouncements? Alternatively, only provide regular updates through a somber and detailed format such as an annual project summary.

I believe in WHO. First, WHO has an unique mandate for supranational coordination. Second, WHO operates by consensus which, while time-consuming and difficult at times, allows countries large and small to have a voice at the table. And finally (related to the previous point), they maintain the trust of ministries of health in a way no other organization does – at least for now… They are losing their reputation by continuing to release shoddy statements backed by limited or poor quality data.

I’ve already complained about science and public health by press release. I understand it though from NGOs but I do not understand this trend from an organization which prides itself as a leader in developing quality health recommendations and soliciting technical excellence.

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A few questions and comments:

The Tropika team reports on the recent WWARN presentation at the MIM conference.

Why is WWARN based at Oxford? A lot of expenses could be saved if the group was hosted, in say New Delhi, where the cost of living is lower and expertise in both malaria and information technology is abundant.

WWARN seems to involve mostly academic researchers. One concern about the viability of any common database is the hesitance of many researchers to share data. Also, much of drug resistance monitoring is conducted directly by national control programs. Will a network of international researchers be able to build credibility with and engage program managers?

Traditionally, the World Health Organization has served to coordinate activities at the supranational level (such as WWARN). WHO is better placed to present itself as a neutral body to promote standardization as well as to request and collate national data. They also have a better relationship with control programs, which would help translate the data into action. Yet, here we seem to have another deliberate effort to bypass them. This is a disturbing trend for the world’s foremost health agency.

Broadly, the molecular mechanisms for resistance are changes in drug targets (which prevent the drug from binding) and changes in transport proteins (which prevent the drug from entering, or pump the drug out of cells). Resistance to artemisinin is not well understood, though some studies have associated increases in the number of copies of a gene called pfmdr1 (a transport protein). The trouble with pfmdr1 is that an increase in the copies of the gene can occur at many sites in the chromosome, and occurs fairly frequently. Thus, if increased pfmdr1 is the primary mechanism of artemisinin resistance, a concept of “containment” may not be valid as resistance would be expected to arise in many locations. Any area which maintains sufficient drug pressure will then select for resistant strains, so the key is to reduce drug pressure. Unfortunately, promoting rational drug use is a difficult task (previously discussed here, and here) but must be, and hopefully will be, included as a component of long-term strategy.

I’ve heard mass drug administration with atovaquone-proguanil is in the works as part of the containment plan. Reaching the migrant gem-mining laborers, particularly those who travel to the Thai-Burma border area, will require some creativity in delivery. The article mentions scaling standard interventions such as insecticide treated nets, but it is not clear what other new strategies will be employed. Regardless of the intervention, improving coordination across the border where there is little infrastructure health or otherwise, might be the most important obstacle to overcome. Agreement between the health agencies of Thailand and Cambodia is great, but I hope the cooperation extends across other government departments which will need to be engaged in this effort. After all, both countries had just recently amassed thousands of troops along their border…

Presently, in vivo efficacy trials are the gold standard for anti-malarial drug resistance monitoring. In vivo trials involve treating a cohort of malaria patients and subsequently checking their blood at regular intervals to detect parasites. Thus, in vivo studies are not direct measures of parasite resistance per se – as other factors such as host immunity and pharmacokinetics play a role, but the outcome (treatment failure) is directly relevant to programs. However, implementing in vivo studies presents several challenges in endemic settings including cost, well-trained staff, lengthy periods of patient follow-up (28 to 63 days), and the need to distinguish treatment failures as recrudescences or reinfections. Since most malaria control programs have limited resources, only a few in vivo trials can be conducted each year. An alternate method to extend the surveillance of antimalarial efficacy is to measure molecular markers of drug resistance.

We employed a molecular surveillance system in Cambodia (Emerging Infectious Diseases Journal – open access) to help detect ACT resistance. This new tool does not replace the standard in vivo trial but rather enables a more efficient use of existing resources. Using this system, a high level of artesunate-mefloquine failures (which were previously believed to be confined to the Thai border) was discovered in the center of the country. Here’s a quick summary of the benefits:

Monitoring changes in antimalarial efficacies is essential for control programs in an era of multi-drug resistance. However, such studies are resource intensive. In Cambodia, for example, the National Malaria Control Program can manage to conduct in vivo studies at only 2-3 sites per year because of limited funds and trained staff. Molecular markers can help target in vivo studies to where they are needed the most. Molecular surveillance is high-throughput and can be performed in a central laboratory on dried blood spots, which are easily collected in the field. Expanded molecular surveillance could also accurately help map anti-malarial resistance and enable sub-national treatment policies in countries with marked geographic variation in drug susceptibility.

What excites me about this work is the translation of molecular knowledge into a monitoring tool for informing policy and improving malaria control operations. I think the last two sentences of the paper say it all:

pfmdr1 assays are now routinely performed in Cambodia by National Malaria Control Program staff. National and regional molecular surveillance by malaria-endemic countries is a real possibility.

In addition the widespread availability of artemisinin monotherapies, near 80% were manufactured after WHO’s intense efforts to convince manufacturers to end production, is particularly worrisome. In many of these areas the bulk of medicines are obtained through private sector channels. Thus, widespread substandard drugs (whether counterfeit or legitimate) will promote clinical failures. These treatment failures have grave implications for increased health burden and increased drug pressure selecting for parasite resistance.

… while treatment using artesunat failed for 7-18 per cent of cases in Dak Lak and south-central Binh Thuan and Ninh Thuan provinces.

While this is likely just bad reporting, the reported information should be verified. Was it an ACT failure or artesunate monotherapy (which will often fail when given alone)? In case of the latter, why were artesunate monotherapy trials still being conducted, or are they just reporting older data? There are many unanswered questions, including the source of the data though the National Institute of Malariology, Parasitology and Entomology was cited earlier in the article. Protecting artemisinin combination therapies is crucial (previous post here) and to my knowledge no widespread ACT failures outside of the Thai-Cambodia border have yet been reported. Let us hope it remains that way, but history has taught us otherwise.