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Comparative efficacy of low-dose versus standard-dose azithromycin for patients with yaws: a randomised non-inferiority trial in Ghana and Papua New Guinea


Yaws, a neglected tropical disease caused by Treponema pallidum ssp pertenue, remains an important public health problem in remote communities of 14 countries in Africa, Asia, and the western Pacific.1x1Mitjà, O, Asiedu, K, and Mabey, D. Yaws. Lancet. 2013; 381: 763–773
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,2x2Mitjà, O, Marks, M, Konan, DJ et al. Global epidemiology of yaws: a systematic review. Lancet Glob Health. 2015; 3: e324–e331
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Yaws is closely genetically related to syphilis, but these diseases can be differentiated on the basis of clinical features and through molecular testing. Yaws predominantly affects children younger than 15 years and transmission occurs by direct contact with a person with an early infectious lesion. The early lesions of primary and secondary yaws predominantly manifest as chronic cutaneous ulcers and papillomas.1x1Mitjà, O, Asiedu, K, and Mabey, D. Yaws. Lancet. 2013; 381: 763–773
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Evidence before this study

We searched PubMed using the terms “yaws”, “treponema”, “pallidum pertenue”, and “azithromycin”, without date or language restrictions. Trials conducted in both Papua New Guinea and Ghana have shown that single-dose 30 mg/kg (maximum 2 g) azithromycin is an effective treatment for yaws. A lower dose of azithromycin (20 mg/kg, maximum 1 g) is recommended by WHO for treatment of trachoma. Observational studies in countries that are co-endemic for trachoma and yaws have shown that mass administration of azithromycin for trachoma reduces the prevalence of both active and latent yaws in the community, but no previous prospective controlled trial has evaluated the relative efficacy of low-dose versus standard-dose azithromycin for the treatment of yaws.

Added value of this study

We investigated the relative efficacy of low-dose and standard-dose azithromycin in the treatment of yaws. By stratifying the trial population on the basis of PCR positivity for bacteria in samples extracted from the patients’ lesions, we provide data on clinical and serological outcomes in active and latent yaws. In participants with active yaws, clinical cure occurred in a similar proportion of participants following treatment with low-dose and standard-dose azithromycin. In participants with active yaws who received low-dose azithromycin, the proportion who achieved serological cure (and therefore the composite primary outcome) did not meet the non-inferiority margin. There was a lower than anticipated serological cure response at 6 months, which reduced the overall power of the study. In participants with presumed latent yaws, serological cure responses did not differ between the treatment groups. Our findings, considered alongside existing observational data, imply that standard-dose and low-dose azithromycin are likely to be equally effective for patients with yaws.

Implications of all the available evidence

20 mg/kg azithromycin seems to be effective in treating yaws. Due to the smaller than anticipated primary study population of Treponema pallidum ssp pertenue PCR-positive participants and the lower than expected serological cure response in both groups, further data are needed before low-dose azithromycin can be unequivocally adopted as the standard of care.

Long-acting injectable penicillin has been the mainstay of yaws treatment since WHO and the United Nations Children’s Fund led campaigns in the 1950s. In 2012, a randomised controlled trial (RCT)7x7Mitjà, O, Hays, R, Ipai, A et al. Single-dose azithromycin versus benzathine benzylpenicillin for treatment of yaws in children in Papua New Guinea: an open-label, non-inferiority, randomised trial. Lancet. 2012; 379: 342–347
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Mass treatment of the community with azithromycin is also key to WHO’s SAFE strategy for the elimination of trachoma as a public health problem;11x11Emerson, PM, Burton, MJ, Solomon, AW, Bailey, R, and Mabey, DC. The SAFE strategy for trachoma control: using operational research for policy, and implementation. Bull World Health Organ. 2006; 84: 613–619
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Although a lower dose of azithromycin might be effective at treating the relatively more metabolically active treponemes in a skin lesion, it might be less effective in latent infections, in which the bacteria are postulated to be less metabolically active.1x1Mitjà, O, Asiedu, K, and Mabey, D. Yaws. Lancet. 2013; 381: 763–773
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We therefore conducted an RCT in Ghana and Papua New Guinea, the countries that report the most cases of yaws globally,2x2Mitjà, O, Marks, M, Konan, DJ et al. Global epidemiology of yaws: a systematic review. Lancet Glob Health. 2015; 3: e324–e331
Summary | Full Text | Full Text PDF | PubMed | Scopus (17)
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