African Sleeping Sickness: A Recurring Epidemic

African trypanosomiasis is making an unwelcome comeback. But unlike other returning diseases, this one has a drug treatment—eflornithine—that disappeared from the market when it failed to cure cancer. Yet like Viagra's origin from a curious side effect in a clinical trial, so too was eflornithine reborn. "When it was discovered that it removes mustaches in women, it suddenly had a market: western women with mustaches," says Morten Rostrup, president of the international council for Medicins Sans Frontieres (MSF, or Doctors Without Borders. Thanks to efforts by MSF, the immediate future for those with sleeping sickness looks considerably brighter than the recent past, but the long-term prognosis isn't clear. The story of the reemergence of this disorder vividly captures the clash between the medical priorities of the developed and developing worlds. The popular name of African trypanosomiasis—sleeping sickness—underestimates the disease's severity. Tsetse flies transmit two subspecies of the pathogen Trypanosoma brucei. The rhodesiense variant, found in southern and eastern Africa, causes acute symptoms, whereas the gambiense variant, common in central and western Africa, is delayed and chronic. Either way, the sickness begins with fever, headache, joint pain, itching, and lethargy, then, as the parasites cross the blood-brain barrier, irritability, confusion, slurred speech, poor coordination, and sensory disturbances ensue. Profound fatigue during the day gives way to extreme agitation at night. Untreated, coma and death invariably follow. ©Serge SilbertThe Culprit: The Tsetse fly is responsible for transmitting variants of Trypanosoma brucei, the African sleeping sickness.Tsetse flies live in vegetation near lakes and rivers, where women and children in search of water are especially vulnerable. The disease is epidemic in parts of Angola, the Democratic Republic of Congo, and southern Sudan, and endemic in nine other African nations. But it wasn't always so. The present epidemic began in 1970, and others occurred from 1896 until 1906 and in 1920. Public health officials squelched the 1920 epidemic by screening and treating people, while "fly boys" swatted flies for a per-bug bounty. In the 1950s, insecticide spraying, brush clearing, relocation of affected villages, and prompt drug treatment controlled the disease. By 1965, it was nearly gone. Then complacency set in. The spraying, clearing, relocating, and treating stopped amid civil wars, political instability, and poverty. The flies returned, and with them, the disease. Societies collapsed. "People depend on the land to eat. If tsetse flies are there, there's no productivity," says Ayoade Oduola, of the University of Ibadan, Nigeria. He also is associated with the World Health Organization's (WHO) Tropical Disease Research Unit in Geneva. Today WHO estimates that about 60 million people in 36 nations live in conditions ripe for African sleeping sickness. Although only 45,000 to 50,000 cases are reported each year, WHO estimates that 10 times that many people are actually sick. Many die undiagnosed, and only 10% are treated in these places where a fly trap can cost more than per capita health care expenditures. But if the infrastructure were in place, there are treatments for African sleeping sickness. From Resurrection Drug to Cosmetic Cream Early drug treatments suramine and pentamidine had severe side effects and affected only one subtype. In 1949 came melarsoprol, described as "arsenic in antifreeze." "We are using this drug today. It corrodes veins and kills 5 to 10% of patients. In some places it is effective in only 30 to 40% of cases, but it usually works in 60 to 70%," explains Rostrup. ©Serge SilbertGetting Treatment: A young boy receives EFLORN sleeping sickness medication through an IV. Eflornithine is less toxic, but requires four intravenous administrations per day, Rostrup explains. The drug was developed in the 1970s by Albert Sjoerdsma at Merrell International Research Center in Strasbourg, France, and by 1980, Cyrus Bacchi, a biochemist at Pace University in New York City, had discovered its effectiveness against T. brucei gambiense. It was used in Africa unofficially and then in clinical trials in the 1980s, and in 1990, the Food and Drug Administration granted it orphan status as a systemic preparation, Ornidyl. So dramatic were recoveries in Africa that it became known as the resurrection drug. But the promise to Sjoerdsma to provide it to treat African sleeping sickness fell through the cracks of several corporate mergers. The last 1,000-dose batch for that indication was manufactured in July 1999. The picture changed dramatically with the discovery that the compound removed hair on female chins. Vaniqa hit the US market in 2001, licensed by Bristol-Myers Squibb from Aventis Pharma in Strasbourg, the latest guise of the corporate mergers. Bristol-Myers Squibb's stated mission is to "extend and enhance human life." But thanks largely to efforts by MSF, 2001 was also the start of a five-year, $25 million collaboration between WHO and Aventis that will supply at least 60,000 doses of eflornithine, for distribution by MSF to treat African sleeping sickness. Bristol-Myers Squibb contributed a year's worth of bulk material to produce the drug. Back to the Bench and Field Despite eflornithine's promise, basic research on T. brucei is critical, particularly because the drug treats only one form in the early stage, is difficult to manufacture and administer, and a vaccine may be impossible. The reason: The pathogen can alter its surface features in nearly 1,000 ways. "People have tried for 20 years. You need an antibody reaction for a vaccine, but the immune system only sees the variant surface glycoproteins," says Sara Melville, a senior research fellow in the University of Cambridge department of pathology who heads the sequencing effort for the largest T. brucei chromosomes, a project shared between the Wellcombe Trust Sanger Centre and The Institute for Genomic Research in Rockville, Md. In May 1994, WHO established the parasite genome networks, which includes T. brucei.1 The parasite has an extraordinarily complex genome. "When we started, we didn't know how many chromosomes it had. We've sorted out the chromosome content, and it has 11 pairs. But it also has 50 to 100 mini chromosomes that are not transcribed unless they are translocated to the larger chromosomes. These are the genes for the surface glycoproteins," explains Melville. Sequencing the genome will, Melville and her colleagues hope, suggest new treatment strategies. Meanwhile, drug discovery continues on other fronts. Several research groups, for example, are developing phosphodiesterase inhibitors that so far destroy T. brucei in cultured cells.2,3 A more ecological approach intercepts the vector.4 In Ethiopia in 2003, government researchers will release 10 million sterile male tsetse flies. If the insects keep females from having young, pasture reclamation may begin as soon as 2005, with total eradication possible by 2018. A pilot test of the "sterile insect technique" in 1997 worked because it targeted an island, Zanzibar, but a similar effort in 1980 in Nigeria and mainland Tanzania failed because the infested area was not isolated. The Organization of African Unity and the International Atomic Energy Agency hope to expand the program to 37 African countries. Research and field tests take time, and thousands are dying now of African sleeping sickness. What will happen when the five-year gift of eflornithine runs out? WHO is negotiating with drug companies to find a manufacturer. Many earlier efforts have failed. ILEX Oncology in San Antonio, Texas, for example, offered to supply eflornithine for $700 per patient, too high a price tag, but continues to evaluate the drug to treat bladder cancer. Melville offers a suggestion: "Perhaps every container of depilatory cream should bear a notice, stating that 10 cents will go to treat African trypanosomiasis. This would make everyone feel just a little bit better." Ricki Lewis (rickilewis@nasw.org)is a contributing editor. References 1. S.E. Melville et al., "The molecular karyotype of the megabase chromosomes of Trypanosoma brucei and the assignment of chromosome markers," Molecular and Biochemical Parasitology, 194:155-73, 1998. 2. R. Zoraghi, T. Seebeck, "The cAMP-specific phosphodiesterase TbPDE2C is an essential enzyme in bloodstream form of Trypanosoma brucei," Proceedings of the National Academy of Sciences (PNAS), 99:4343-8, April 2, 2002. 3. A. Rascón et al., "Cloning and characterization of a cAMP-specific phosphodiesterase (TbPDE2C) from Trypanosoma brucei," PNAS, 99:4714-9, April 2, 2002. 4. N. Bhalla, "Pan African group takes lead against the tsetse fly," The Lancet, 357:686, Feb. 23, 2002.

African Sleeping Sickness: A Recurring Epidemic

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