Clinical and Health Affairs
Advances in Global Biotechnology and Local Resources to Treat Malaria
By Ann M. Campagna, M.D., and Mrinal M. Patnaik, M.D.
Abstract
The global campaign toward malaria eradication has received a tremendous boost with the addition of artemisinin compounds to the therapeutic armament. Artemisinin drugs are now being recommended in combination with existing antimalarials, a pairing often referred to as artemisinin-based combination therapy (ACT). The World Health Organization considers ACT first-line treatment for uncomplicated malaria in endemic regions. In the United States, ACT is not currently FDA-approved. The Walter Reed Army Institute of Research, however, is studying its use and developing artemisinin compounds for the treatment of severe malaria. Artesunate, one of the artemisinin derivatives, is available to eligible patients in the United States free of charge. The drug is stocked at the CDC headquarters, as well as at 7 of the 20 quarantine stations.
Malaria continues to be one of the top causes of morbidity and mortality worldwide. One child dies of malaria every 30 seconds. Each year, between 300 million and 500 million cases of malaria occur, mostly in sub-Saharan Africa. Of those, between 1 million and 3 million are fatal. Much of the burden falls on African children younger than 5 years of age.1 Pregnant women are also at higher risk. Acute and severe clinical disease are responsible for more than 200,000 cases of fetal loss and more than 10,000 maternal deaths annually.2
In the United States, 1,564 cases of malaria were reported to the Centers for Disease Control and Prevention (CDC) in 2006. Six of those were fatal.3 In Minnesota, 268 cases were reported to the Minnesota Department of Health between 2000 and 2006, with an average of 38 cases reported each year. Of those cases, 73% occurred in persons born outside the United States (86% of those were born in Africa). Of the 268 cases, 88% were further identified by species of the parasite causing it, with Plasmodium falciparum being responsible for 59% of cases.4
The vast majority of malaria cases in the United States occur because of noncompliance with preventative measures. Among U.S residents travelling to malaria-endemic regions in 2006, for whom prophylaxis information was known, 67% reported that they had not received chemoprophylactic drug therapy.3
The Artemisinin Story
Malaria has developed resistance to many commonly used treatments. Geographic areas are specifically defined by their resistance to certain agents. The newest class of drugs being used for malaria control is the artemisinins. The derivatives of this base drug used in combination with existing antimalarials are referred to as artemisinin-based combination therapy or ACT.
Artemisinins are derived from the qing hao plant, more commonly known as sweet wormwood (Artemesia annua). A Chinese handbook of prescriptions for emergency treatment from 340 A.D. recommends adding a handful of qing hao to 1 liter of water to cure fevers. In 1596, Chinese medical texts referred to using qing hao to treat malarial fever. In 1971, qing hau sau, the active ingredient from qing hao, was isolated from the wormwood tree; that ingredient is now known as artemesinin. Its various derivatives include artesunate, artemether, artemotil, and dihydroartemisinin.5
Artemisinin is highly effective against malaria. It rapidly takes action against the parasite in both the sexual and asexual stages with minimal toxicity to the patient. It is the only antimalarial drug with minimal clinical resistance. The major limiting factor is the high recrudescence rates, secondary to their short half-lives. Therefore, drugs derived from artemisinin are always used in combination with longer-acting agents such as mefloquine, amiodioquine, sulfadoxine/pyrimethamine, and lumafantrine. The World Health Organization considers ACT first-line treatment for uncomplicated malaria in most countries in which the disease is endemic.2,6 The organization has called for a ban on oral artemisinin monotherapies in order to prevent people from becoming resistant to ACT.
As with many malaria treatments, the cost of drugs derived from artemisinin is a tremendous barrier to their use in much of the developing world. (The cost of ACT ranges from $1.50 U.S. to $2.50 U.S. per dose.) Because of the need and the cost, a counterfeit market thrives, and counterfeit manufacturers produce up to 50% of artemisinin-based drugs distributed in Africa and Asia. Although counterfeit drug markets have been a long-standing concern in regions in which malaria is endemic, they are also a concern within the large southeast Asian and East African communities in the Twin Cities. Many people are inadequately treated with ineffective counterfeit medications while traveling to their home countries, resulting in increased morbidity and mortality.
The Artemisinin Project is a partnership involving the Bill and Melinda Gates Foundation, Amyris Biotechnologies, the Institute for OneWorld Health, and the University of California, Berkeley. Its goal is to inexpensively produce artemisinin through fermentation and chemical synthesis.1 This is expected to lower the cost of ACT by decreasing the production cost of artemisinin derivatives. The cost of artesunate from recombinant DNA is $0.25 U.S. per dose, compared with $2.50 U.S. per dose for that derived from the extract of wormwood trees.
Lowering the cost not only will bring treatment to more people but also will close the profit margin on counterfeit operations. Thus far, the partners have engineered E. coli to produce an artesunate precursor, amorphadiene, and found the gene that converts this precursor into artemisinic acid. They have also developed a yeast strain of Saccharomyces cerevisiae, which is capable of producing high levels of artemisinic acid. However, more work remains to be done in order to be able to produce artemisinin derivatives on a larger scale.
An Investigational Drug Becomes Available
In the United States, the FDA has not yet granted approval for ACT, as the country is not considered a malaria-endemic area. However, the Walter Reed Army Institute of Research is studying the use of artesunate to treat severe malaria. Several other large-scale studies have supported the use of artemisinin-based over quinine-based care (Table).5
Approximately 10% of the cases reported annually in the United States are considered severe, defined as acute disease with severe organ dysfunction or high levels of parasitemia. Until June 2007, IV quinidine gluconate was the only parenteral treatment available in this country for severe malaria. Its side effects, most notably cardiac toxicity, make it less favorable as an antimalarial agent.
Researchers at Walter Reed are making artesunate available through the CDC as an investigational new drug to eligible patients in the United States free of charge. The drug is stocked at the CDC headquarters, as well as at 7 of its 20 quarantine stations.7 For a patient to receive artesunate, he or she must have severe malaria, have high levels of malaria parasites in the blood, be unable to take oral medications, lack timely access to IV quinidine, have a quinidine intolerance or contraindications, or have experienced quinidine failure.5
Minnesota physicians need to know that timely diagnosis remains the most important part of treatment. Malaria should be on the top of the differential diagnosis for any patient who has recently traveled to a country in which the disease is endemic, even up to 2 months following their return home.
The CDC quarantine station at the Minneapolis/St. Paul International Airport currently does not carry artesunate. The location nearest to the Twin Cities that stocks it is Chicago O’Hare International Airport. If you have a patient with severe malaria, contact the CDC at 770/488-7788 or 770/488-7100 (after hours) and request to speak with the CDC Malaria Branch. The CDC will then send artesunate out on the next available flight going nearest to the destination city. The receiving hospital arranges for pick up at the airport and transports the drug to the hospital. Among cases to date in the United States, the average time from artesunate request to patient’s first dose is 7 hours.
If you have questions regarding confirmation of diagnosis or if you need additional recommendations for treatment, contact the Minnesota Department of Health’s Acute Disease Investigation and Control Section at 651/201-5414 or 877/676-5414.
Conclusion
Minnesota has a growing international community. As health care providers, we need to be aware of the cutting-edge technologies that could help our immigrants, international travelers, visitors, and their families. We need to consider malaria as a possibility for any patient who presents with a fever and has traveled to a country in which malaria is endemic, and we need to know how to quickly and efficiently get those with severe disease the best treatment possible. MM
Ann Campagna is a medicine and pediatrics resident at the University of Minnesota. Mrinal Patnaik is a fellow in hematology and medical oncology at the Mayo Clinic School of Medicine in Rochester.
References
1. Hale V, Keasling JD, Renninger N, Diagana TT. Microbially derived artemisinin: a biotechnology solution to the global problem of access to affordable antimalarial drugs. Am J Trop Med Hyg. 2007;77(6Suppl):198-202.
2. World Health Organization. Malaria Fact Sheet. Available at: www.who.int/mediacentre/factsheets/fs094/en/index.html. Accessed January 13, 2009.
3. Mali S, Steele S, Slutsker L, Arquin PM. Centers for Disease Control and Prevention. Malaria surveillance—United States, 2006. MMWR Surveill Summ. 2008;57(5):24-39.
4. Minnesota Department of Health. Minnesota Refugee Health Provider Guide. Available at: www.health.state.mn.us/divs/idepc/refugee/guide/index.htm. Accessed January 13, 2009.
5. Centers for Disease Control and Prevention. Notice to readers: New medication for severe malaria available under investigational new drug protocol. Morbid Mortal Wkly Rpt. 2007;56(30):769-770.
6. Rosenthal PJ. Artesunate for the treatment of severe falciparum malaria. N Engl J Med. 2008;358(17):1829-36.
7. Arguin PM, Weina PJ, Dougherty CP. Artesunate for malaria. N Engl J Med. 2008;359(3):313.