Opinion | Treating the Tsetse’s Curse

On March 20, 1990, a previously healthy man returned to the U.S. after a 10-day safari in Kenya, Tanzania, and Rwanda. He was in my hospital’s emergency department just 6 days later with a fever of 104, a magenta nodule on his arm, and — unbeknownst to him — millions of sinuous, single-celled parasites swimming in his blood.

His diagnosis? African trypanosomiasis, commonly called sleeping sickness. But not the West African form transmitted by tsetses that slowly invades brains over months to years; instead he had the East African tsetse-borne form due to Trypanosoma brucei rhodesiense.

The latter infection sometimes moves like wildfire, killing patients before parasites ever reach their brain.

Such was our fear for our patient Tony Browne, who was both desperately sick and wide awake on that fateful day in 1990. In fact, he was so wide awake that — once he knew what he had — he quickly called his lawyer and updated his will. As a stopgap, Browne then received pentamidine while awaiting another antiparasitic treatment stored at CDC. Then, 24 hours later, having finally started on an old, toxic drug called suramin, Browne underwent a spinal tap, which came back entirely normal.

Thank God, I remember thinking at the time, because now I would not have to tell him that what he really needed was an even scarier arsenical drug called melarsoprol, whose painful injections for a Stage Two (neurologic) infection with T. b. rhodesiense could not only make brave men cry but also carried a one in 10 risk of causing a reactive, often-fatal encephalopathy.

Now fast forward to December 2023: a press release from an international non-profit called Drugs for Neglected Diseases initiative (DNDi) announced an infinitely easier oral treatment for East African trypanosomiasis in blood and brain. But first, some backstory.

A Short History of a Long-Time Terror

In Microbe Hunters, a bestselling book first published in 1926, author Paul de Kruif, PhD, includes a vivid chapter about Sir David Bruce, the dogged British researcher who not only discovered Brucella (a genus of bacteria that causes undulant fever in cows, pigs, sheep, and humans) but African trypanosomes.

Bruce also grasped (but never fully proved) that blood-sucking tsetse flies were the vectors of the scourge whose toll on Africa was by then undeniable. In addition to many smaller flurries of illness, an epic wave of sleeping sickness killed 300,000 to 500,000 people in and around the Congo Basin and Uganda between 1896 and 1906. Since then, other outbreaks have periodically struck Africa as recently as the late 1990s.

Furthermore, nagana, a trypanosomal blight of cattle and equines, has continuously deprived much of Africa of livestock that might otherwise be eaten, milked, or used as draft animals, thus hobbling rural economic development.

Now for some happier news. Along with better screening for human disease, the last few decades have also witnessed progress in controlling tsetse flies. Breakthroughs include the release of sterile males to limit reproduction, to better traps to contain their spread, to 2014’s decoding of the tsetse genome, which is now aiding research on how to possibly block trypanosomes’ transmission from fly to man.

Countering these triumphs, however, is the threat of rising transmission due to climate change, not just because heat accelerates tsetse breeding but, as Serap Aksoy, PhD, a tropical medicine researcher at the School of Public Health at Yale University, recently told me, “temperature increases…are a really good thing for the parasite.”

In her own insectary at Yale, which typically houses between 2,000 and 3,000 pregnant female tsetses at any given time, Aksoy has observed that higher temperatures nearly halve the number of days between experimental infection of flies and the detection of parasites in their salivary glands.

How to Develop a Drug for a Neglected Tropical Disease

For doctors caring for underserved people in the global south, it’s no surprise that modern anti-parasitic drugs are hard to come by. After all, what pharmaceutical company wants to develop a new treatment from scratch for a disease that almost exclusively afflicts the tropical poor?

Fortunately, soon after receiving the 1999 Nobel Prize for Peace, leaders at Médecins Sans Frontiѐres (MSF — known in the U.S. as Doctors Without Borders) realized — in the words of Bernard Pécoul, MD — that “MSF did not have the medicines…needed to carry out our lifesaving work.” Four years later, MSF launched DNDi with Pécoul at the helm and African trypanosomiasis topping the list of urgent priorities.

This brings us to fexinidazole, the 10-day oral treatment that is now replacing both suramin and melarsoprol.

Early work began with DNDi collecting roughly 800 nitroimidazole compounds and identifying fexinidazole as the most promising oral cure based on experiments in mice.

In 2009, a Phase I trial in healthy, sub-Saharan volunteers determined the correct dosing at concentrations deemed effective. Phase II/III trials in the Democratic Republic of Congo and Central African Republic established clinical efficacy after 2 million people were screened and 749 treated. As part of a public-private partnership with DNDi, Sanofi then donated the drug to WHO, which in turn, provided the drug to endemic countries where patients receive it for free. In 2018, fexinidazole was approved in Europe for use in West African sleeping sickness, and by FDA in 2021.

But, as I recently learned from Spanish physician Olaf Valverde, MD, the East African form was more difficult to study until 45 patients from Malawi and Uganda (35 with Stage 2 neurologic infection) were found and treated. This led to last December’s “positive scientific opinion” of fexinidazole by the European Medicines Agency as the first oral treatment for acute rhodesiense sleeping sickness.

“You must have a great feeling of satisfaction,” I said to Valverde, who has served as DNDi’s Clinical Project Manager for African sleeping sickness since 2009. “More than satisfaction,” he replied with feeling, adding what a privilege it was to “accompany the full clinical development of fexinidazole” and witness its impact on patients.

Clinical Coda

To this day, Tony Browne has a knot in his forearm from the severe phlebitis that followed his first injection of suramin. But more importantly, even now, he sees his battle against T. b. rhodesiense as a major turning point in his life.

“I really think that when I was lying in bed at UCLA, I actually saw that guy at the door you see as death,” he recently said. “And I was right on the edge, and I thought, ‘Well, I’ve had a great life. If I die, fine… but I would really like to keep living.’ So I had to fight it and stay alive and not get a reaction to the medication.”

How wonderful that far more patients in Africa will now have that same second chance at life.

To learn more about fexinidazole and meet an infected African patient, watch DNDi’s 7-minute video entitled “A Doctor’s Dream: A pill for sleeping sickness.”

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