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.

In the latest issue of Emerging Infectious Diseases (CDC – open access), Wrongsrichanalai and Meshnick report the declining efficacy of artesunate-mefloquine along the Thai-Cambodian border. (A full disclaimer: Dr Steven Meshnick is my mentor). This border is the traditional birthplace of most drug resistant strains, and it is no surprise that the first widespread reports of ACT failures arrived from here. The failures are probably due to endemic mefloquine resistance generated by years of prior use rather than resistance to artesunate itself though we cannot exclude that possibility. There’s an important lesson for policy makers here: ACTs with partner drugs which have pre-existing resistance in that area will fail rapidly. Early last year SEARO, the Southeast Asia regional office for the WHO, held a meeting on the “Containment of Malaria Multi-Drug Resistance on the Cambodia-Thailand Border” to discuss this challenge. Unfortunately, for people living along the Thai-Cambodia border few therapeutic options remain.

Kenya was the only market where Lapdap was being sold and GSK was developing Dacart with the Medicines for Malaria Venture (MMV), an interesting public private partnership model which seeks to mitigate some of the financial risks associated with drug development (well illustrated in this case). Still, it’s an unfortunate development to lose treatment options, but there were other concerns with these drugs. While Lapdap and Dacart’s toxicity in certain patients are well acknowledged, their cross resistance with another antifolate, sulphadoxine-pyrimethamine (SP), is a significant impediment as well. SP, which also inhibits folic acid synthesis, has been used worldwide for decades and SP resistant strains exist in many places in sub-Saharan Africa. The same molecular mechanisms which confer SP resistance, point mutations in the dhfr and dhps genes, confer Lapdap resistance. Thus, the therapeutic life of Lapdap and Dacart would be compromised in areas with preexisting SP resistance. Research by Dr. Alisa Alker (a former mentor of mine) and others have shown the presence of these mutations in sub-Saharan Africa whose prevalence would have rapidly increased in the face of increased drug pressure. Lapdap and Dacart are gone, but they may have not been the best of options in the first place.

At a population level, overdiagnosis is expensive for the health system due to the increased wastage of antimalarials and increased demand on provider time. The former concern is more pronounced recently since many countries are now using expensive artemisinin-combination therapies. Increased drug pressure also facilities the emergence and spread of drug-resistant malaria. Drug-resistant malaria increases morbidity and mortality and in some regions of the world our therapeutic alternatives are alarmingly few. I research the epidemiology and mechanisms of antimalarial resistance, and thus the lack of emphasis on parasitogically confirmed treatment is particularly worrisome. A leading malaria researcher once wrote to me, “The problem is even key malaria scientists still have difficulty thinking about how to prevent drug resistance development and how important it is to improve diagnosis and health care infrastructure so that “rational drug use” can be reinforced. They only think about what alternative drugs should be now that this one fails….” Words to heed indeed.