Three doses of a cheap, common antibiotic batter—but don’t beat—yaws, a tropical skin disease

One year ago, the World Health Organization (WHO) declared yaws—a little-known, painful, and disfiguring tropical disease—a target for global eradication by 2030. Today, results from a clinical trial involving 56,000 people have shown just how challenging it will be to achieve that goal.

The trial’s ambitious regimen—giving an entire population three doses of the inexpensive antibiotic azithromycin at 6-month intervals—worked much better than WHO’s current strategy, which recommends a single dose of azithromycin followed by targeted azithromycin treatment of people who develop the disease’s hallmark skin ulcers, as well as their contacts. But the more intensive treatment did not eliminate the disease from the population, as researchers had hoped it would.

The three-dose regimen leads to “a tremendous reduction” in disease, says Oriol Mitjà, an infectious disease researcher at the Germans Trias i Pujol University Hospital in Barcelona, Spain, who led the study. “It’s positive. And the way to go for eradication. But we did not achieve eradication.”

“It’s a very important piece of work,” says Sascha Knauf, a neglected tropical disease researcher at Germany’s Friedrich Loeffler Institute, who was not involved with the research. But, Knauf adds, the results show that eliminating yaws in humans won’t be easy. “It’s not just going out and giving these people some tablets, and that’s it.”

Yaws, a blight on poor, rural communities in countries in equatorial Africa, Asia, and the Western Pacific, is caused by a subspecies of the Treponema pallidum bacterium called pertenue, a close cousin of the organism that causes syphilis. It mainly affects children and spreads by skin contact. Although not fatal, it is painful, and it can invade underlying cartilage and bones. Left untreated, it can lead to disfigurement, lifelong disability, and social stigma.

WHO first set up a campaign to wipe yaws off the face of Earth in the 1950s. The plan fizzled in part because the treatment—an injection of benzathine benzylpenicillin in the buttocks—is painful and cumbersome. The eradication drive got new life when Mitjà showed in a 2012 paper in The Lancet that a single azithromycin tablet works just as well.

Seven countries are now carrying out programs to blanket affected areas with a single-dose treatment, using some of the 153 million doses of azithromycin donated by EMS, a Brazilian drugmaker. After such campaigns, health workers visit the communities at regular intervals, looking for people with telltale ulcers and retreating them and their contacts to mop up remaining infections.

But a study published in 2015 by Mitjà and colleagues, also in Papua New Guinea, showed this regimen did not get rid of the bacterium entirely. A 2018 follow-up report revealed that yaws was making a comeback, and a few patients carried a strain of T. pallidum that had become resistant to azithromycin.

In the current trial, Mitjà and colleagues—with the extensive help of local field teams in Papua New Guinea—applied the standard regimen in 19 administrative areas in New Ireland, home to more than 30,000 people, and the three-dose regimen in another 19 areas with more than 26,000 people. Six months after the last dose, they visually examined all participants for ulcers, confirming they were caused by yaws with polymerase chain reaction testing.

The result: The single-dose approach reduced prevalence of active yaws by 65%, the three-dose regimen by 91%, they report today in The New England Journal of Medicine. The three-dose treatment course was also twice as effective at reducing latent yaws, a stealth form of the disease that can follow an active case and can cause skin ulcers to re-erupt at any time.

“This paper shows clearly that one dose is not enough. You need to give three,” says David Mabey, a physician at the London School of Hygiene & Tropical Medicine who heads WHO’s Scientific and Technical Advisory Group for Neglected Tropical Diseases. “Three doses is not that hard to give considering it’s oral. But we need the funding. We need the surveillance. We need mapping to know where the cases are.”

Part of the problem may have been that the campaign didn’t reach enough people. WHO’s strategy for one-dose campaigns calls for at least 90% coverage, a tall order in poor, rural areas. But coverage in the study ranged from 64% to 87% per treatment dose, partly because a tropical cyclone at the time of the second dosing caused roadblocks and reduced access to many villages. Eradication is out of reach if researchers can’t get higher than 70% or 80% coverage, says Sheila Lukehart, who studies treponemal infections at the University of Washington, Seattle. “That’s the key.”

Lukehart is also worried about drug resistance. In the new study, researchers sequenced bacteria found in all 10 children in the three-dose group who still had active ulcers 18 months after they received the first dose. Three of them carried an azithromycin-resistant version of the bacterium.

Such resistance is already a major problem with the T. pallidum cousin that causes syphilis. “Azithromycin, though a very convenient treatment, can’t be used for syphilis in much of the world. You don’t want that to happen with yaws,” Lukehart says. “This has to be monitored very, very carefully. … Every round of mass treatment could select for resistant strains.”

Still, Mabey says, the three-dose regimen “will certainly [be] on the agenda” when his WHO advisory group meets in the near future. Kingsley Asiedu, who heads WHO’s yaws eradication effort, says the new evidence must be reviewed together with other studies as part of WHO procedures for guideline development, before it can become part of the global yaws strategy. Any formal change, he adds, could take at least 1 year.