COVER STORY
PREVALENT After World War II, malaria eradication efforts succeeded in many parts of the world but not in most of Africa, many parts of Asia, and South America
Malaria cases per 100,000 • 10 or fewer D10 25,000 NOTE: As of January 2004. SOURCE: World Health Organization, Malaria Department
FIGHTING MALARIA New antimalarial drugs are needed to ensure that effective and affordable treatments continue to be available and are not lost to parasite resistance ANN M. THAYER, C&EN HOUSTON H E R E ARE ESSENTIALLY N O P A T I E N T S W I T H
malaria on the planet that I can't treat and cure if they come to me the first day they have symptoms," says Stephen L. Hoffman, M.D., former director of the Malaria Program at the Naval Medical Research Center. "If they come to me after they have severe malaria, no matter what I do, at least 10% of them will die." Hoffman, a past president of the American Society of TropiWWW.CEN-ONLI NE.0RG
cal Medicine & Hygiene, notes that "there is a drug out there for everybody." The issue is not one of availability but of identifying who needs the drugs, getting the drugs to them when they are needed, and making the drugs affordable. "And we're not quite sure how you do that," he adds. More than 4 0 % of the world's population, much of it very poor, lives in areas where malaria is a risk. Looking now toward prevention rather than treatment, Hoffman created Sanaria, a start-up company working to develop a malaria vaccine (see page 85). According to the World Health Organization (WHO), between 300 million and C & E N / OCTOBER 24, 2005
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500 million clinical cases of malaria occur every year. Recent empirical estimates have suggested the total could run as high as 660 million (Nature 2005,434,214). Malaria is estimated to kill more than 1 million people annually and possibly as many as 3 million, with most of the deaths among children under age six living in sub-Saharan Africa. The health and economic toll is tremendous. Political, economic, and societal factors affecting health care and government involvement in malaria prevention and control are significant factors. Despite decades of fighting malaria, the disease is gaining ground as the parasite's resistance to drugs and the parasite-carrying mosquito's resistance to insecticides expand. Malaria in humans is caused by one of four species of the Plasmodium parasite, which can be transmitted by about 60 species of Anopheles mosquito. P. vivax is the most widespread parasite, occurring largely in the tropics and throughout Asia, but it causes a less severe form of the disease than P. falciparum. About 90% of malaria-related deaths occur in Africa and are caused by P. falciparum. If one survives multiple infections in childhood, such exposure leads to a natural immunity that limits the severity of the disease. This immunity will wane without continued exposure to infection. Pregnant women have reduced immunity. Malarial parasites enter a human host when a female mosquito feeds. Infectious sporozoites quickly migrate to the liver, where they develop and multiply. This asymptomatic incubation phase can last from a week to months. Only when the parasites emerge from liver cells and invade red blood cells—where they multiply, burst from the cells, and infect new blood cells—does the infection result in the fever, flulike symptoms, and anemia associated with malaria. A SMALL PERCENTAGE of infections become severe and lead to organ failure, seizures, coma, and death. Meanwhile, some parasites mature into reproductive gametocytes that are ingested by a feeding mosquito. In the insect gut, they develop into oocysts that grow and release sporozoites, which make their way to the mosquito's salivary glands, completing the cycle. Local, regional, and international ef-
forts have mobilized to support the development and implementation of preventive measures—such as environmental cleanup, insecticide spraying, treated bed nets, and immunizations—and treatments, including diagnostics and medicines. The effectiveness of such programs continues to be
FRUITFUL Artemisia annua, or sweet wormwood, is the source of the potent, fast-acting antimalarial drug artemisinin. scrutinized and debated. The Global Fund to Fight AIDS, Tuberculosis & Malaria (GFATM) and Global Alliance for Vaccines & Immunization (GAVI) are among organizations stepping up to purchase the needed measures. In 1997, the Multilateral Initiative on Malaria (MIM), an alliance of agencies, institutes, and governments, was formed to maximize the impact of scientific research through capacity building in Africa and global collaboration. The following year, W H O , the United Nations Children's Fund (UNICEF), the U N Development Program, and the World Bank launched Roll Back Malaria (RBM) Global Partnership to coordinate efforts in fighting malaria. RBM today involves 90 countries, companies, and other organizations. It recently published its "World Malaria Report 2005" on progress toward halving the burden of malaria by 2010. For decades, malaria has been treated widely, but not always appropriately, with drugs that fall into three broad categories. Aryl aminoalcohol compounds include quinine, quinidine, chloroquine, amodiaquine, mefloquine, lumefantrine, and piperaquine.
"Cheap and effective treatment for malaria with one drug is no longer an option for most countries in Africa/'
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COVER STORY Other treatments are antifolates, often using a dihydrofolate reductase inhibitor—such as pyrimethamine, proguanil, and chlorpro-
ited the drug therapies that can be used, as is the case for chloroquine. For a few drugs, such as halofantrine, side effects
ISSUES Resistance and safety can limit the effectiveness of antimalarial drugs ANTIMALARIAL
YEAR INTRODUCED
RESISTANCE FOUND
Quinine Chloroquine Proguanil Primaquine Sulfadoxine-pyrimethamine Amodiaquine Mefloquine Artemisinins Halofantrine Atovaquone Lapdap
19th century 1945 1948 1950 1967 1975 1977 1970s 1988 1996 2003
1910 1957 1949
OTHER LIMITATIONS
Compliance, safety
Safety 1967 1982 1992 1996
Safety, possibly resistance Cost, safety Compliance, cost, possibly safety Cost, safety Cost Resistance potential
SOURCE: Medicines for Malaria Venture, World Health Organization
guanil—with a sulfa drug, such as dapsone or sulfadoxine. The last major category is artemisinin and its derivatives: artesunate, artemether, and dihydroartemisinin. In some areas, a growing resistance among malaria parasites has seriously lim-
have been an issue. Since 2001, WHO has recommended specific combinations of at least two drugs—one preferably an artemisinin derivative—for treating falciparum malaria in all countries experiencing resistance to single-drug therapies.
Any two drugs used in combination should have independent modes of action and different biochemical targets in the parasite, WHO says, and their ongoing effectiveness should be closely monitored. No reported clinical resistance has yet developed to the artemisinin derivatives, which are highly potent, fast acting, and well-tolerated. Many hope that artemisinin-based combination therapy (ACT) will improve efficacy and prolong the usable life of the combined drugs by delaying the onset of resistance. ACTs now available cost up to $2.40 per course of treatment, which makes them at least 10 times more expensive than many older drugs, such as chloroquine. Prices at present are out of the reach of many who need the drugs, especially in Africa. Despite the higher cost ofACTs, more than 50 malaria-endemic countries have policies to adopt them; many nations will use them as a first-line treatment, and about half have begun implementing these policies. All the required treatments are expected to cost at least $300 million to $500 million per year. The Institute of Medicine has recommended that international organizations and world leaders create a global an-
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