The parasite strikes back
There were about 216 million cases of malaria last year and an estimated 655,000 deaths in 2010 according to the World Malaria Report 2011. Most deaths occur among children in Africa where a child dies every minute from malaria. Resistance to treatment adds to these statistics.
Resistance to artemisinin - a vital component of drugs used to combat the most severe form of malaria - has been reported in a number of countries in Southeast Asia, including Cambodia and Thailand, says the WHO, which authored the report. In September, it was reported that resistant areas may now include central Vietnam and southeastern Myanmar.
Nick White, professor of tropical medicine at Mahidol University in Thailand, and the University of Oxford, confirms that "resistance is spreading, but it is not clear how far". Observations suggest that although there are changes in parasite sensitivity to artemisinin, artemisinin-based combination therapy (ACT) remains clinically effective for the treatment of Plasmodium falciparum malaria, the most deadly and one of the most common strains.
Since 1994, ACTs have been saving millions of lives in the developing world. While 90 per cent of malarial deaths occur in sub-Saharan Africa, the disease occurs in more than 100 countries, with more than 200 million clinical cases per year. Children under five, and pregnant women, are most at risk.
Experts agree that without global resistance containment efforts, including an increase in funding and research, recent progress in malaria control could be threatened. Last year, there was a shortfall of approximately US$4 billion needed to fully control malaria and contain artemisinin resistance. This urgency is heightened by the fact that there is nothing in the pipeline, nor are there any alternatives that could offer the same level of efficacy as ACTs.
White believes there is much talk about the importance of funding research efforts related to resistance containment, "but there is no clear commitment from international donors".
Artemisinin is a compound isolated from a traditional Chinese herb called qinghao or Artemisia annua. It has been used for thousands of years in traditional Chinese medicine for relief of intermittent fever. Rediscovered by Chinese doctor and researcher Tu You-you in 1972 as a promising replacement for another anti-malarial drug, Chloroquine, artemisinin derivatives are the most efficacious treatments today.
It is administered in combination with another conventional anti-malarial drug to slow the development of parasite resistance. Researchers and scientists believed that until the discovery of an effective malaria vaccine, the development of new anti-malarial drugs, primarily from artemisinin, will continue to be the only weapon in the global fight against malaria.
Harald Noedl, associate professor at the Medical University of Vienna and head of the experimental tropical medicine and field research unit is concerned. "The potentially devastating implications of resistance to a drug class to which there is currently no real alternative call for cost-effective strategies to extend the useful life spans of currently available anti-malarial drugs," he says.
Many aspects of artemisinin resistance are still not well understood. But the Global Plan for Artemisin Resistance Containment (GPARC) has made many assumptions that have also become the strategic foundation for containment.
Recommendations for eliminating the threat of artemisinin resistance include: ensuring consistent, accurate diagnostic testing; removing substandard or counterfeit anti-malarial drugs; providing affordable, quality assured ACTs versus cheaper and more dominant oral monotherapies typically used; and, according to Dr Andrea Bosman, co-ordinator for WHO's global malaria programme, discovering the molecular marker for artemisinin resistance.
Finding the marker is a high priority and "core focus" of many of the top scientific labs around the world. "Labs all over the world are collaborating to find the answer. Once qualified, a molecular marker could be used in surveillance," says Bosman. "We have found clearance of the parasites much slower in the Mekong sub-region - three to five days when it should take 24 hours, and this can lead to full resistance, but it hasn't spread." Bosman doesn't believe the era of artemisinin is over, but there is a lot of work to be done. "We don't want to lose artemisinin, which is a highly effective class of drugs, as we don't have anything else to replace it," Bosman says.
According to the WHO, fewer than 30 anti-malarials are under development from the preclinical stage to Phase IV, and only a limited number of these are potential replacements for artemisinin-based therapies.
Noedl believes researchers "lost the initiative in the late 1990s and early 2000s, partly due to the widespread belief that artemisinin-based combination therapy would take us through to eradication. Major efforts to develop novel combination therapies not based on artemisinins are required."
Medicines for Malaria Venture (MMV) in Geneva has a mission to develop new affordable anti-malarial drugs. Currently, MMV is testing a non-artemisinin-based drug, which if successful, could deliver a new combination therapy in place of ACTs in five years' time.
Another team of researchers from the Johns Hopkins University published a study last month showing how a new artemisinin-derived combination in a single, oral dose shows promise in mice.
Simplifying the complex regimens of combination therapies into a single dose would improve patient compliance, another factor contributing to the risk of parasite resistance to artemisinin.
But there is little time to wait for incremental gains. "Pre-clinical studies could be anywhere from five to seven years away, and nine out of 10 studies are eliminated before they even it make it to drug application," says Bosman.
Professor Richard Haynes, who is a principal investigator for the Hong Kong University of Science and Technology, has a different view on the potential resistance catastrophe. He describes how "none of the current ACTs have evolved based on an understanding of how the individual components actually kill the malaria parasite."
Haynes and his researchers believe they have discovered how artemisinins kill the malaria parasite and are looking critically at a more practical choice for the partner drug in the combination therapy.
Haynes is optimistic, but frustrated by the politicising.
"There has been so much politics from vested interests - large research and development groups who seem incapable of admitting differing viewpoints. It has been very disappointing. The loss of efficacy of the current ACTs is an emerging catastrophe. We will lose the only effective means of controlling malaria on such a wide scale," Haynes says.