Can We Defeat Neglected Tropical Diseases?

I recently heard it said that mankind’s extermination of the smallpox virus, lauded as it is, was a feat of under-appreciated endeavor. The evolutionary necessity to survive is, after all, overwhelming. Given our destruction of many species due to a drive to dominate every aspect of the planet, is killing off one little virus that big a deal? Probably yes, because unlike most of humanity’s victims, smallpox virus, like other human pathogens, chooses us as its habitat, and this is the critical environment our own drive to survive will take efforts to sustain. So, eradicating the smallpox virus, without eliminating its environment, has indeed been an extraordinary feat. The failure, so far, to extinguish other human pathogens is less surprising that it might seem, given our ability to create vaccines, drugs, and to avoid germs through advances in public health. Although progress has been slow, we are now on the cusp of eliminating several terrible plagues.

Two different infectious diseases are currently vying for the top spot to join smallpox on the extinction list, and a third has come into view. Leading the way is Guinea worm, or Dracunculiasis. The disease is caused by parasitic nematode worms. Females, just a few millimeters in width, can reach a meter in length. Larvae of the worm are transmitted in tiny water fleas, which enter the intestines of people drinking infested water. The larvae survive within our stomach, mature, and then crawl out through the intestinal wall to wriggle their way to our subcutaneous tissues. The pain associated with the migrating worms can be excruciating, although the disease is seldom, if ever, fatal. When male and female worms meet, they mate. The males then die, but the pregnant female then waits until she senses her victim is in water (often accelerated by the burning sensation patients have due to the inflammatory trail she leaves whilst migrating beneath the skin). There, she bursts through the skin to release her larvae in water to infect water fleas for further transmission.

No drugs exist for Guinea worm. Treatment involves capturing the female as she protrudes from the skin and slowly winding her out of the body, often using a matchstick. In the mid-1980s, an estimated 3.6 million people were infected with Guinea worm. Last year, there were just 28 reported cases. Dealing with Guinea worm has involved massive public health efforts centered on educating people in endemic regions to always filter water, for example, using a cloth, which will retain the water fleas and block transmission. Former US president Jimmy Carter has been the leading advocate of Guinea worm eradication. A blip has occurred in the drive to eradication, though. A few years ago it became clear that dogs could also harbor Guinea worm, adding a complication to our ability to break transmission forever, although optimism remains that we will within a few years finally eliminate this disease.

Running neck and neck with Guinea worm is polio, a viral disease. The virus is present in infected peoples’ feces, which, if entering fresh water, can infect others who drink it or eat food that has been in contact with that water. Most people harboring polio virus suffer no ill effects. Sometimes, however, it affects muscle and the nervous system leading to paralysis. Franklin D. Roosevelt was wheelchair-bound by polio. As President of the USA, he initiated the world’s first “crowdfunding” campaign, with the “March of Dimes” in 1938, asking people to donate small amounts of money to help seek cures. Research led to the development of successful vaccines, one based on dead versions of the virus and the other on living versions that had been attenuated or changed in ways that stopped them causing disease.

It was the latter that found most use, leading to the elimination of the disease in many parts of the world. Back in the 1980s, however, over 350,000 cases were still reported worldwide in spite of the vaccines. This triggered, in 1988, a global effort to eliminate the disease. Vaccines were distributed widely, under the jurisdiction of the World Health Organisation. Success has been prolific: 2018 saw only 27 cases reported. However, the year before had seen just 22, spread across three countries (Pakistan, Afghanistan and Nigeria). Last year’s cases included those in these three countries but Somalia, Kenya, the Democratic Republic of Congo, Niger, and Papua New Guinea all reported cases too. The decline in incidence may be faltering, and efforts need to be redoubled to re-seize the initiative against polio, too.

As both the Guinea worm and polio eradication programs were marking their first great successes through the 1980s and 1990s, another disease called human African trypanosomiasis, or sleeping sickness, was showing the reverse trend. The disease, caused by tiny single-celled parasites called trypanosomes, which are injected into people by blood-sucking tsetse flies, starts with general symptoms like a fever as the parasites proliferate in the bloodstream of its victims. In time, however, the parasites invade other organs, including the brain. Neurological disorders ensue. Patients become depressed, even psychotic, and sleep-wake patterns change, causing victims to sleep at random times, hence its common name. Africa’s indigenous populations had learned to avoid the tsetse fly, and it was only with the European colonization of Africa starting in the late nineteenth century that the first great sleeping sickness epidemics started, as people were forcibly moved into tsetse areas to farm. In parts of Uganda, for example, a third of the population died of the disease in the early years of the twentieth century. The discovery of the parasites, and the realization that tsetse flies transmit the disease allowed interventions with drugs and fly-killing methods, and by the 1960s, the disease was largely under control.

However, as African economies declined and competing health problems grew, sleeping sickness was forgotten and the disease saw a resurgence in the later part of the twentieth century. By the late 1990s, around 300,000 people were estimated to be infected. Drugs used to treat the disease were poisonous; one based on arsenic actually killed one in twenty who took it, irrespective of the disease. And yet, as resources were being diverted into the big killers of the tropical world, particularly malaria, HIV, and tuberculosis, few people were prepared to engage with sleeping sickness. The World Health Organization classified sleeping sickness among the neglected tropical diseases as they set out to reverse the trend. Other organizations, notably Médecins Sans Frontières (MSF), whose doctors were at the frontline fighting the disease, also felt new action was needed. The horribly toxic arsenic-based drug was losing efficacy as drug-resistant parasites spread.

A new drug, eflornithine, had been introduced in 1990 and was highly active against the disease, but it was, according to manufacturers, too expensive to produce given neither its victims nor the health services in the countries where they lived could afford to pay for it. Eflornithine had been invented with the hope of curing cancer. One study showed that when mice with skin cancer were treated with the drug the hair on their backs, that had been removed when inducing experimental cancer, didn’t grow back. Eflornithine, it seemed, could prevent hair growth. So wealthy women in the western world, embarrassed by the presence of unwanted facial hair, offered a new and potentially lucrative market for the drug and its manufacture recommenced. MSF fought a skillful campaign to let the world know that a drug that no-one would produce to treat a killer disease was now being made to prevent the growth of unwanted facial hair!

Global outrage ensued. Even the pharmaceutical industry acknowledged the problem. Aventis, (now Sanofi) agreed to provide eflornithine for free to WHO along with money to support control programmes. Other drugs companies started to offer drugs for free for sleeping sickness and other tropical diseases, too. The Drugs for Neglected Diseases initiative (DNDi) was founded in Geneva in 2003 to seek new and better drugs for trypanosomiasis and other diseases for which the industry had no incentive to seek new therapies. Another agency, the Foundation for Innovative New Diagnostics (FIND), also emerged in Geneva looking for better ways to diagnose patients with HAT. New programs to attack the tsetse fly were launched, too. The Gates Foundation funded a consortium led from the University of North Carolina to seek new drugs. One compound made it through phase II trials, during which hundreds of thousands of people were screened and treated if affected, and although that drug failed ultimately because it induced kidney disease in some people taking the drug, the campaign, alongside the WHO-led screening efforts, began to hit the disease.

The tide turned. By 2018 fewer than 1,500 cases of the gambiense type of human African trypanosomiasis (gHAT) were reported. Another form of the disease, caused by a related but different parasite endemic in east and southern Africa, rhodesiense HAT, has fewer than a hundred cases too. With current tools already proving effective against HAT, a further boost came at the end of 2018 when the European Medicines Agency approved the use of fexinidazole, a compound first shown to be active against trypanosomes by Frank Jennings in Glasgow in the 1980s, and picked up by DNDi two decades later to develop as an orally available drug that can cure the disease, even when parasites are found in the brain.

As part of their road map for the control or elimination of neglected tropical disease, WHO had set a date of 2020 to eliminate gHAT as a public health problem (defined as reducing incidence to fewer than one case per 10,000 people in endemic zones). The campaign is on target to reach that goal, with a tantalizing possibility of also bringing sleeping sickness to eradication. As the polio and Guinea worm campaigns have stagnated, the HAT campaign could even catch up, although it is easy to see the rate of decline slowing as the end game comes in sight. It has recently been shown that asymptomatic people can harbor trypanosomes in their skin, and an animal reservoir that can serve as a refuge for the parasites may exist. Notwithstanding, in all of these campaigns and others targeting different tropical diseases, successes are accruing, the primary risk now coming from reversals in the kinds of international cooperation and activity that has led to these successful attacks on diseases of the poorest people in the world. Efforts should be redoubled now to beat these terrible scourges of mankind.

These findings are described in the article entitled The elimination of human African trypanosomiasis is in sight: Report from the third WHO stakeholders meeting on elimination of gambiense human African trypanosomiasis, recently published in the journal PLOS Neglected Tropical Diseases.