Re-emergence of yaws after single mass azithromycin treatment followed by targeted treatment: a longitudinal study

Abstract

Background: Yaws is a substantial cause of chronic disfiguring ulcers in children in at least 14 countries in the tropics. WHO's newly adopted strategy for yaws eradication uses a single round of mass azithromycin treatment followed by targeted treatment programmes, and data from pilot studies have shown a short-term significant reduction of yaws. We assessed the long-term efficacy of the WHO strategy for yaws eradication.

Methods: Between April 15, 2013, and Oct 24, 2016, we did a longitudinal study on a Papua New Guinea island (Lihir; 16 092 population) in which yaws was endemic. In the initial study, the participants were followed for 12 months; in this extended follow-up study, clinical, serological, and PCR surveys were continued every 6 months for 42 months. We used genotyping and travel history to identify importation events. Active yaws confirmed by PCR specific for Treponema pallidum was the primary outcome indicator. The study is registered with ClinicalTrials.gov, number NCT01955252.

Findings: Mass azithromycin treatment (coverage rate of 84%) followed by targeted treatment programmes reduced the prevalence of active yaws from 1·8% to a minimum of 0·1% at 18 months (difference from baseline -1·7%, 95% CI, -1·9 to -1·4; p<0·0001), but the infection began to re-emerge after 24 months with a significant increase to 0·4% at 42 months (difference from 18 months 0·3%, 95% CI 0·1 to 0·4; p<0·0001). At each timepoint after baseline, more than 70% of the total community burden of yaws was found in individuals who had not had the mass treatment or as new infections in non-travelling residents. At months 36 and 42, five cases of active yaws, all from the same village, showed clinical failure following azithromycin treatment, with PCR-detected mutations in the 23S ribosomal RNA genes conferring resistance to azithromycin. A sustained decrease in the prevalence of high-titre latent yaws from 13·7% to <1·5% in asymptomatic children aged 1-5 years old and of genetic diversity of yaws strains from 0·139 to less than 0·046 between months 24 and 42 indicated a reduction in transmission of infection.

Interpretation: The implementation of the WHO strategy did not, in the long-term, achieve elimination in a high-endemic community mainly due to the individuals who were absent at the time of mass treatment in whom yaws reactivated; repeated mass treatment might be necessary to eliminate yaws. To our knowledge, this is the first report of the emergence of azithromycin-resistant T p pertenue and spread within one village. Communities' surveillance should be strengthened to detect any possible treatment failure and biological markers of resistance.

Funding: ISDIN laboratories, Newcrest Mining Limited, and US Public Health Service National Institutes of Health.

Figure 1. Characteristics of PCR-confirmed active yaws by epidemiological history, molecular type, and macrolide resistance mutation

PCR-confirmed active yaws refers to samples with positive results in either tpN47 (tp0574) or tp0548, and in which the pertenue subspecies was confirmed by TprL PCR amplicon size. *A random sample of 90 (out of 690) clinically suspected yaws cases at baseline and 84 (out of 121) at 6 months were tested by PCR; we provide data on the characteristics of lesions that were actually PCR-positive among the subset of PCR-tested lesions (31 at baseline and 41 at 6-months). In 12-month to 42-month surveys, we tested all clinically suspected lesions by PCR; therefore we provide data on the characteristics of all lesions detected for these time-points. †Not all T. p. pertenue positive samples could be fully typed for all three typing targets. § P<0.0001 for the estimate of the mean evolutionary diversity of T. p. pertenue isolates at 24-month survey compared to baseline. ¶ Estimate of the mean evolutionary diversity of T. p. pertenue isolates at each round. ‡Not all T. p. pertenue positive samples could be amplified for 23S rRNA by PCR.

Figure 2. Yaws lesions in a patient with treatment failure associated with macrolide-resistant Treponema pallidum subsp. pertenue

(A) Primary lesion (red, moist 2·5 cm ulcer) on the left leg of an 11-year-old patient with yaws observed at the 30 months survey. Lesional swab PCR was positive for T. p. pertenue with wild-type 23S rRNA. (B) Secondary yaws papillomas (multiple nodules with yellow-colour granular surface) seen at 36 months survey. These lesions were PCR positive for T. p. pertenue with A2059G mutation in 23SrRNA. (C) Photomicrograph of skin biopsy of the larger papilloma lesion in Panel B with abundant spirochete organisms stained bright red by the Treponema pallidum immunohistochemical stain (×400 magnification).