The Globe and Mail: A legendary killer allowed to get away

By André Picard

OMUGO, UGANDA - Wiltred Draberu's minuscule body is racked by fear-induced convulsions. He is wailing uncontrollably, and it's no wonder. Four strangers in white lab coats are gathered around the one-month-old, each holding a limb, and one of them is brandishing a menacing-looking syringe.

They are trying to inject him with a mixture of arsenic and antifreeze, a substance so toxic it can kill him, so caustic it can burn gaping holes in his flesh.

When, on the fourth try, the team finds a vein and finally injects the substance, a burning sensation shoots through the baby's body and directly to his racing heart, redoubling his terror.

The members of this quartet are not torturers, but medical personnel for Médecins Sans Frontières, the Nobel Prize-winning humanitarian group that works in areas ravaged by war and infectious disease.

They are giving Wiltred the first of 21 daily doses of melarsoprol, the only treatment for someone in the advanced stages of a scourge that has haunted Africa for generations: sleeping sickness.

More than a century ago, a British bacteriologist discovered that the dreaded parasitic disease was transmitted by the tsetse fly. But that knowledge did not prevent the deaths of millions of people, felled as colonialists opened up new fields and croplands.

Finally, by 1965, concerted control measures such as burning and trapping the tsetse - often with "fly boys" who stood out as bait to attract the bugs - had the disease almost eradicated.

However, sleeping sickness has bounced back mightily. Over the years, civil and political unrest eroded the war on disease so that it is now a daily threat to 60 million people in 36 sub-Saharan countries, most notably Sudan and the Democratic Republic of Congo.

Some epidemiologists believe the region is on the cusp of the worst epidemic ever, but, in the struggle for health-care dollars and media attention, sleeping sickness remains a poor cousin to Africa's familiar triumvirate of killers: HIV-AIDS, tuberculosis and malaria.

Its name may seem benign, but the disease is not.

Early symptoms of sleeping sickness are banal: headache and fever. But, within months, sufferers can be in the grips of a bizarre form of insomnia; they sleep all day and are up all night. The condition can degenerate quickly into insanity before an infected person slips into a profound coma and dies.

Treatment for the disease is almost as tortuously cruel as the symptoms. Melarsoprol is so caustic that it melts regular syringes; glass ones have to be used. It also burns the skin so that it must be injected at a different location each time. Once the drug is diluted in the bloodstream, however, it does not cause that sort of damage.

"It's very painful for me to realize that the only drug we have is one that can kill my patients," says Olema Erphas, the clinical assistant at the Omugo Sleeping Sickness Centre in northeastern Uganda.

Still, patients like Wiltred are the lucky ones. Fewer than four million people at risk have access to diagnosis or treatment, and the options are quickly running out.

The tried-and-true drugs to treat sleeping sickness are not only punishing to take, they also are becoming ineffective because the parasite is developing resistance. New drugs are unaffordable and, increasingly, unavailable.

Wiltred's mother, 27-year-old Sally Brateru, also has the disease. She was treated with melarsoprol, which didn't kill her - but neither did it cure her. She is among the one-third of infected in the area who have a resistant strain.

As her boy screams just a couple of metres away, Ms. Brateru winces, but cannot go to his side. She is tethered to the bed, receiving an around-the-clock intravenous drip of something called difluoromethornithine (DFMO).

DFMO works so well that it has been nicknamed the "resurrection drug." But it costs 10 times more than melarsoprol, or almost $600 (U.S.). Worst yet, production has been discontinued because, at that price, some of the poorest people in the world can't afford to buy enough of the drug to make it profitable.

At the 58-bed Omugo centre, they are literally counting down the world's supply of DFMO. As the nurse loads up Ms. Brateru's IV drip, 1,812 vials are left. When her course of treatment is done, there will be 1,805 and counting.

Then the drug of last resort could well be gone.

Wiltred and his mother are victims of the world's growing pharmaceutical gap. Their unenviable situation has been dubbed by some activists as pharmacological apartheid.

Dr. James Orbinski, a Canadian who heads Médecins Sans Frontières, says bluntly that the "market has failed them" and tens of millions of other around the world.

It is unconscionable that the poor are being left to die because corporations do not deem it profitable enough to develop and manufacture drugs that would save them, Dr. Orbinski says.

To date, the debate has centred on making drug cocktails available to people in developing countries with HIV-AIDS. The focus has been patent laws, and finding ways to institute differential pricing.

At a cost of more than $20,000 (U.S.) annually, these drugs would remain largely inaccessible even after dramatic price cuts. They are also a treatment, not a cure.

But some companies have started, for public-relations reasons, to give away selected drugs. It is easy to do, given that they are already making huge profits off most HIV-AIDS medicines.

With sleeping sickness, the issue of drug access is both more clear-cut and far more complex. A few hundred dollars can buy a cure. But there is no market in the developed world to drive research and production.

The maker of DFMO, the U.S. subsidiary of Aventis SA, a multinational corporation based in Switzerland, has stopped producing the drug because it can make a lot more money by using its facilities otherwise.

The company is not protecting its patent; on the contrary, it has turned the rights over to the World Health Organization.

But WHO cannot find a manufacturer. The precursor chemical of DFMO is unstable so it requires specialized workers; the drug is corrosive, requiring special piping and a dedicated production line, and demand will never be in the millions of doses.

Groups such as Médecins Sans Frontières argue that multinational drug companies should be willing - or compelled - to eat the losses for so-called orphan drugs (those with a small client base but life-saving benefits) because they make so much money overall.

MSF recently launched a daring and politically charged campaign aimed at shaming pharmaceutical companies and the countries that regulate them into doing more to make life-saving drugs available in developing countries.

But the bottom line does not have a heart.

Pharmaceutical products aimed at the maladies of the developing world - even if they saved millions of lives - could never hope to generate the profits of drugs that help those in developed countries achieve firmer erections or slow hair loss.

Drug companies expect to make a minimum of $200-million a year from new products. The good ones bring in $1-billion a year or more.

The statistics are telling. According to WHO, of 1,223 new drugs patented from 1975 to 1997, only 13 targeted tropical diseases that are deadly scourges in Africa, Asia and Latin America. Nine of those drugs were developed by the U.S. Army and the balance by veterinary researchers.

Less than 0.2 per cent of the $27-billion the pharmaceutical industry invests annually in research is allocated to the tropical diseases that account for almost one in five deaths on the planet.

Even in Omugo, one of the more isolated places in the world, citizens cannot escape the vagaries of the marketplace.

The only real hope for a dramatic change is a breakthrough such as the development of a vaccine, and one Canadian researcher with a small government grant has been trying to make that a reality for more than 20 years.

"Right now, there is no effective vaccine for any parasitic disease, and that's a real tragedy," says Terry Pearson, who has been toiling away at the University of Victoria. "But parasites are much more clever than bacteria and most viruses, so we have our work cut out for us."

Sleeping sickness will kill at least 350,000 people this year, and if the budding epidemic takes root, it will kill millions more.

The blood-sucking tsetse fly, which looks like a small horsefly, can carry two different strains of the sleeping-sickness parasite (trypanosomiasis brucei gambiense and trypanosomiasis brucei rhodesiense) from one person to another, quickly infecting entire villages.

Like many infectious diseases, sleeping sickness primarily affects those who struggle to live. In 11 of the 16 countries where there are currently outbreaks, the per-capita gross national product is less than $1,000.

It thrives where there is civil unrest, a lack of surveillance and a breakdown in the provision of basic health services.

A conventional control program such as spraying is not effective because the female tsetse fly lays only one egg every three months and there is no regular laying season.

The insect lives in the shade of trees near waterways, an ideal stalking ground. The poor feel the tsetse's bite as they head to the river to wash their clothes, into the fields to harvest and into the woods to flee war. Babies, strapped to their mothers' backs, are particularly vulnerable to the bites.

One of Justo Ezama's chores is to fetch water twice a day from the Enyau River. He also gathers firewood nearby. And when the seven-year-old can steal a few moments to play, he likes to dive into the cool waters and play hide-and-seek on the fringes of the jungle.

Justo has come to the Omugo treatment centre to be tested for sleeping sickness. His father, a tobacco farmer, has reluctantly taken time away from the harvest because of the boy's worrisome behaviour.

He has been falling asleep regularly in school, roaming the house all night and "talking nonsense" with increasing frequency - all classic signs of the neurological effects of the disease.

The laboratory technician first pricks the boy's finger to gather a few drops of blood. Mixed with a reagent, the test shows that the parasite is present.

Next, a vial of blood is drained from an arm of the whimpering Justo for a more detailed examination of the plasma. That, too, is positive, the whipped-shaped parasites clearly visible under a microscope. The schoolboy has sleeping sickness.

But his ordeal is not over. He will also require a spinal tap to determine if the illness has reached the advanced stage and found its way into the central nervous system and the brain.

By the time the needle is being jabbed into the base of his spine, Justo is sobbing. A nursing assistant is clutching him tight, ensuring stillness; one slip of the needle could result in paralysis.

Meanwhile, Justo's father is explaining, rather unconvincingly, that it is all for the best. The news is bad and, the next day, the schoolboy will begin melarsoprol treatment.

Until Médecins Sans Frontières established its sleeping-sickness program in 1986 (and, a decade later, the local treatment centre), those who contracted the disease were left to die.

In that short period, the humanitarian group has been able to bring a raging epidemic to manageable levels and almost to the point of local eradication.

In this part of northern Uganda, sleeping-sickness rates hit an astonishing 25 per cent a decade and a half ago. Now, the rates are down around 0.4 per cent. (Just across the border in Sudan, there is a raging epidemic, and the disease claims more victims than HIV-AIDS.)

For Carole Boireaux, head of the sleeping-sickness project, the Ugandan numbers are proof that public-health programs can succeed, even in the most trying of conditions.

"The fact that sleeping sickness is so complex, and local circumstances so trying, yet we are still able to control spread of the disease should really give us hope," she says.

Despite her optimism, however, there are many reasons to be pessimistic.

Until HIV-AIDS hit epidemic proportions in the late 1980s, no disease, except arguably malaria, had as devastating an economic and social impact on Africa as sleeping sickness.

The tsetse fly made the continent's richest soil unharvestable. The parasite has made raising livestock south of the Sahara virtually impossible. And epidemics have been frighteningly lethal: In a single year, 1906, more that four million people died in Uganda alone. Epidemics in 1915 and 1940 killed half a million more each, despite widespread burning and trapping programs.

Yet as colonialism waned so did research and control programs for parasitic diseases such as sleeping sickness and malaria, and they spread unchecked for decades.

There was an upswing of interest again in the heady Sixties when groups such as the Rockefeller Foundation tried to get scientists interested in the "great neglected diseases of mankind." In 1965, sleeping sickness was virtually eradicated. It was one of the great public-health successes of modern time - almost.

As the African map was redrawn in a Cold War game of chess, disease control took a back seat to economic and political considerations. The tumult created an ideal climate for the deadly return of sleeping sickness.

In 1977, having just finished postdoctoral studies and unable to find work in Canada, Terry Pearson took a job at the International Livestock Research Institute in Nairobi. It was there he discovered "tryp," one of the most beguiling and devastating parasites known to man.

Three years later, Prof. Pearson moved from working with bovine strains of the disease to the human ones, and has been toiling away ever since, thanks largely to grants from the Natural Sciences and Engineering Research Council of Canada.

Along the way, he has become one of the world experts on sleeping sickness. "I guess that over the years we've done quite a few things," the University of Victoria professor says modestly.

In reality, he and his collaborators have developed new diagnostic tests and made steady progress toward developing a sleeping-sickness vaccine, a goal that has eluding scientists for more than a century since the parasite was discovered.

Prof. Pearson and his team are trying to outsmart the parasites by first learning precisely how they function, deconstructing them molecule by molecule.

The goal is to learn the intimate details of antigenic variation, a process that allows parasites to alter their surface molecules, or coat. By doing so, they disguise themselves, confusing the body's immune response.

"The African trypanosome is a classic example of a parasite changing its coat every time. It's very tricky," Prof. Pearson said.

By the time the human body can detect the parasite that causes sleeping sickness, the levels in the blood are extremely high. The immune system fights them off, but the survivors adapt, create new coats and multiply again. The process is repeated over and over again until the immune system wears out.

Prof. Pearson says the African trypanosome can create more than 1,000 coats. That makes it virtually impossible to develop a vaccine.

What he, in conjunction with researchers at the International Livestock Research Institute, the University of Brussels and the University of Massachusetts, are trying to do is identify the molecules that remain relatively stable as the parasite mutates and to target them.

They have zeroed in on a tiny region called the flagellar pocket, where the parasite takes up nutrients. By creating a vaccine that targets that molecule, researchers think that they can starve the parasite and keep it from reproducing. So far, the process has worked in laboratory mice.

"This is a long way from the marketplace," Prof. Pearson says. "But to put it into context, you have to understand that since the causative agent was identified 105 years ago, there has not been a single vaccine candidate - until now."

If it were not bad enough that treatments are few and a vaccine is non-existent, one cannot forget that sleeping sickness is one of the most expensive, time-consuming and stubborn diseases to tackle on the ground, says Pierrette Caron, a veteran MSF nurse.

"It's expensive to do the testing that detects the disease, it's expensive to treat and it's expensive to do surveillance to see if the program is working. Those are not very attractive traits in countries where spending on health care is negligible and there are many other problems to tackle," she says.

Ms. Caron has dedicated more than a decade of her career to battling the devastation wrought by the tsetse fly because she cannot imagine a greater challenge as a health professional.

"Sleeping sickness is one of the most interesting diseases imaginable - it's a challenge epidemiologically, medically, biologically, socially and politically. It's one of the world's greatest public-health challenges," she says.

The project in northern Uganda is the most costly MSF has ever undertaken, and it does not have the cachet - and the ability to attract donors - of high-profile interventions in war zones.

When the group was awarded the Nobel Peace Prize, the money was used to established the MSF Fund to Fight Infectious Disease, underscoring the organization's commitment to long-term strategies to combat tropical diseases.

Ms. Boireaux says that knowing there is such a deep-seated commitment makes it easier toil away in virtual anonymity in harsh settings such as Omugo.

Like a military general, she systematically tracks the spread of the disease and sets out to meticulously "sterilize the human reservoir" - detecting and treating all cases in a given area.

Every week, mobile clinics are dispatched over spine-crushing roads to villages where virtually all residents are tested. Those who test positive for sleeping sickness are immediately whisked to the treatment centre.

"You can't afford to leave even one behind," Ms. Boireaux says, "because, if we do, the cycle of infection can begin again."

Convincing the infected to get help is not easy, particularly when those in the early stages feel fine. The treatment is long - 10 to 23 days - and harsh. To woo patients, MSF charges nothing and feeds them, practices that are unusual in African hospitals.

Patients in the early stages of the disease, when the parasite is in the blood but has not yet invaded the central nervous system, are treated with pentamidine. The daily intramuscular injection, given in the backside, is painful. It also requires a 10-day hospital stay, quite a sacrifice for a subsistence farmer or a mother with six children.

Treatment for the advanced stage is even less attractive. The melarsoprol regime lasts three weeks. Each injection not only hurts, it makes patients physically ill. In up to 10 per cent of cases, it can cause encephalopathy, a swelling of the brain that is often fatal.

"For this gentleman, things did not go so well," Mr. Erphas, the clinical assistant at the Omugo centre, says as he points to a 31-year-old man lying comatose on a metal bed. The hospital is an elongated mud hut with a thatched straw roof; it has no doors or windows.

A day earlier, Dimo Phili had been lively and alert, albeit stark-raving mad. Nurses tied him to the bed because he was sneaking out at night and destroying crops, such as the peanut field he single-handedly devoured.

But the treatment, his only hope for a cure, poisoned him.

"With all the knowledge we have, I always wonder why we can't have a better drug, a newer drug," Mr. Erphas says as he strokes the patient's hair. Later that day, the man would die.

Melarsoprol has been around since 1949. The reason newer drugs have not come along is that research by pharmaceutical corporations is virtually non-existent. Much more effort has gone into the search for treatment of the form of sleeping sickness that affects animals, namely cattle and horses, than the disease that kills humans. (Sleeping sickness kills an estimated $5-billion(US) worth of livestock annually.)

Worse yet, the manufacturer has repeatedly threatened to discontinue production because the drug's profit margin is low. Still, a course of treatment costs many times more than the per-capita health spending in Uganda.

Pentamidine was another drug well on its way to being phased out until it was found to be effective in treating pneumocystic carinii pneumonia, a common symptom of HIV-AIDS. Overnight, the price of the drug increased tenfold.

Médecins Sans Frontières and WHO were able to negotiate a reprieve. Pentamadine has been offered at the old price - about $120 (U.S.) for 10 shots - on the understanding that it be used only for the treatment of sleeping sickness.

But the deal has expired and, over the next four years, it will rise again to the market price - stratospheric by the standards of developing countries.

The situation with DFMO is even more dramatic. It was discovered accidentally by cancer researchers, but it works amazingly well, curing virtually every patient who has had a relapse of sleeping sickness. (Maddeningly, however, it does not work as a first-line treatment, but only on parasites that have developed a resistance to melarsoprol.)

DFMO was approved as a treatment for sleeping sickness in 1990, but production was discontinued in 1995, again because of lack of profitability. After much badgering, the manufacturer agreed, earlier this year, to produce one last batch, 8,000 vials of the life-saving medication.

The Omugo Sleeping Sickness Centre received 2,000 of them.

When Sally Brateru began her treatment, there was enough of the drug to treat fewer than 300 patients.

For her, the countdown seems particularly perverse. If and when Wiltred needs DFMO to combat a recurrence of sleeping sickness, she wonders, will there be any of the drug left?

As Olema Erphas watches a nurse carrying the crying child back to the mother's soothing breast, he ponders the question at length. And, as eloquent as he is, the best he can come up with is a shrug.

Then, staring as the baby suckles himself to sleep, he adds dejectedly: "Ideally, there should be more and better drugs, but the world seems to have forgotten this disease, it seems to have forgotten us."

THE DISEASE

Two types of sleeping sickness affect humans: One caused by the protozoan parasite Trypanosoma brucei gambiense and the other by Trypanosoma brucei rhodesiense.

Both are spread solely by the tsetse fly. (A cousin that preys on cattle can travel via the common stable fly and has spread to Indonesia and the West Indies.)

SYMPTOMS

The tsetse's bite is painful and can produce, in a week or two, a red sore or chancre. Weeks to months later, other symptoms appear, such as fever, a rash, swelling around the eye and hands, headaches, extreme fatigue, aching muscles and joints and, in some cases, swollen lymph nodes on the back of the neck.

As the illness progresses, wasting is common. Personality changes, irritability, loss of concentration, progressive confusion, slurred speech, seizures and difficulty in walking and talking can occur when the infection invades the central nervous system.

Sleeping patterns may change until the patient lapses into a coma (hence: sleeping sickness) and eventually dies, usually from respiratory failure.

PREVENTION

There is no vaccine or preventive drug. The parasite is extremely good at evading the human immune system, using "antigenic variation" to mutate and defeat antibodies.

THE RISK

Sleeping sickness endangers 60 million people in 36 sub-Saharan countries. It will kill at least 350,000 people this year.

Visitors to Africa are at risk only if they travel extensively in rural areas, where the tsetse fly is found in thick woods near water. Insect repellents are not effective and it is wise to sleep under netting and to wear thick drab clothing (the fly can bite through thin fabric and is attracted to bright and very dark colours).

Vehicles should be inspected for flies before entering and a person should not ride in the back of anything open as the tsetse is drawn to the dust vehicles kick up.

SOLUTIONS

Fly fighting: Campaigns to eradicate the tsetse have failed. But a biologist in Zimbabwe discovered recently that the fly is attracted to compounds found in the breath of cattle. Traps using the compounds as bait have eliminated the tsetse from much of a Zimbabwean wildlife park, but they are costly to maintain and the fly soon reappears if they are not.

Drugs: Those used most often are very toxic and all too frequently kill the patient. There is little financial incentive to develop new ones.

Research: Science needs to identify metabolic pathways, enzymes and antigens that are specific to the organism. At present, attempts to do this spend about 0.001 per cent of the amount invested in research on cardiovascular disease.

Sources: U.S. Centers for Disease Control, University of Western Ontario, Out of My Life and Thought, by Dr. Albert Schweitzer.