WHO strategy to eradicate yaws should be revised to achieve elimination, study suggests

First evidence of antibiotic resistance in yaws bacteria highlights need for robust vigilance and improved laboratory surveillance.

In 2012, WHO began rolling out its strategy to eradicate yaws – a bacterial disease of the skin, bones, and joints that has re-emerged over the past 20 years in tropical parts of Africa, Asia, and South America. However, new research assessing the long-term efficacy of this approach in a high-endemic community in Papua New Guinea, reveals that the strategy needs to be revised to achieve yaws elimination.

In the study, elimination efforts were hampered by the relapse of untreated latent infections (where bacteria are present but do not show noticeable symptoms) in individuals who were absent at the time of mass treatment, and to a lesser extent, by the re-introduction of yaws cases from in-migration.

The findings, published in The Lancet, also provide the first evidence of emerging drug-resistance, with bacteria resistant to azithromycin, the first-line antibiotic for yaws treatment.

“Drug resistance is unlikely to be common, and resistant cases were resolved by a single dose injection of benzathine benzylpenicillin. Our findings highlight the importance of treating every person in a community to be sure of reaching all latent infections. Doing multiple rounds of mass treatment may be necessary to eliminate yaws”, says lead author Dr Oriol Mitjá from the International SOS Lihir Medical Centre, Lihir Island, in Papua New Guinea, and the Barcelona Institute for Global Health in Spain.

Yaws is caused by the bacterium Treponema pallidum, closely related to the one that causes syphilis. It is spread by direct contact with minor injuries (i.e., cuts, scratches) on the skin and afflicts mostly children. It initially causes skin lesions, but if left untreated, can become a chronic, relapsing disease that leads to severe deforming bone lesions. Today, about 89 million people are living in endemic regions.

A previous attempt at eradication between 1954 and 1964 was unsuccessful. During this time, WHO and UNICEF treated 50 million active cases and contacts in 46 countries with penicillin. However, in untargeted latent cases the infection was able to recur, and the disease gradually re-emerged in the 1970s.

WHO’s strategy to eradicate yaws by 2020 involves a single round of mass treatment with the inexpensive antibiotic azithromycin followed by targeted treatment programmes comprising active case detection every 3–6 months to identify and treat all symptomatic cases and their contacts.

This new study builds on previous research which showed that large-scale administration of one oral dose of azithromycin to almost 84% (13,490) of 16,092 residents of Lihir Island in Papua New Guinea (whether thought to be infected or not) dramatically reduced yaws prevalence from 2.4% to 0.3% within six months. This low prevalence remained unchanged a year after mass treatment.

In this new analysis, all residents of this island community were followed for an additional 30 months (up to 3.5 years after initial treatment) between April 2013 and October 2016. Every 6 months, molecular testing was used to detect Treponema pallidum to confirm the prevalence of active disease and to monitor the emergence of resistance to azithromycin. The researchers also used genotyping to differentiate between indigenous and imported cases.

Following mass administration of antibiotics (coverage rate 84%) and targeted treatment programmes, PCR-confirmed active yaws prevalence fell from 1.8% before mass treatment to a low of 0.1% after 18 months. But after two years, the infection began to re-emerge, rising to 0.4% at 42 months.

In children aged 1 to 5 years old, a sustained drop in seroprevalence – the level of the pathogen identified in the population (latent yaws) – following mass treatment, and in genetic diversity of yaws strains (between 24 and 42 months) was noted, indicating an overall drop in transmission.

At each 6-month survey, more than 60% of the total burden of yaws was found in individuals who were not at mass treatment. Migrants and residents who travelled to other endemic areas after mass treatment made up less than 28% of cases at each survey.

Importantly, researchers recorded five cases of azithromycin-resistant yaws harbouring the macrolide-resistant A2059G mutation. All five children lived in the same village and were related to, or in contact with, the first (index) case, suggesting that they had all been infected with a single macrolide-resistant strain.

According to Dr Mitjá, “Our findings suggest that a single round of mass treatment with azithromycin may not be sufficient to eradicate yaws. What’s more, for the first time, clinically significant resistance to azithromycin has developed in yaws bacteria as a result of exposure to the antibiotic. To speed up global eradication efforts, the WHO strategy needs to be adapted to achieve coverage rates of higher than 90%; incorporate repeated rounds of mass treatment; treat a much broader geographical area; and improve drug resistance monitoring to prevent the spread of antibiotic-resistant strains.”

The authors note that the findings of the study may not necessarily be generalizable to other highly-endemic countries with different environmental and cultural characteristics. For instance, in communities bordering areas where the disease is endemic, there are likely to be higher numbers of imported yaws cases than the isolated island community studied as part of this analysis.

Dr Michael Marks, Assistant Professor & NIHR Clinical Lecturer at the London School of Hygiene and Tropical Medicine, and an expert on yaws, commented:

“The study team were able to relatively rapidly contain the drug resistant strain using penicillin, demonstrating the effectiveness of the research team and the high-quality surveillance they had in place to detect these strains early and intervene with penicillin before the problem escalated.

“The concern, I think, would be that this was a research study on a relatively speaking a small number of people (20,000) with good access to testing. When MDA is scaled up to programmatic level, the same level of monitoring and oversight will be much more difficult to maintain and therefore resistance could emerge and not be detected as rapidly.

“However, this is a very impressive piece of work, which demonstrates the value of large scale field evaluations for neglected tropical diseases and of following up those programmes for a prolonged period of time. The data generated will undoubtedly inform WHO policy on yaws eradication.”