Low-dose versus standard-dose azithromycin for treatment of yaws
Authors: Lenka Mikalová, David Šmajs
Journal: The Lancet Global Health (2018)

In their Article in The Lancet Global Health, Michael Marks and colleagues1Marks M Mitjà O Bottomley C et al.Comparative efficacy of low-dose versus standard-dose azithromycin on patients with yaws: a randomised non-inferiority trial in Ghana and Papua New Guinea.Lancet Glob Health. 2018; (published online Feb 15.)http://dx.doi.org/10.1016/S2214-109X(18)30023-8Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar compare the efficacy of low-dose azithromycin (20 mg/kg) versus standard-dose azithromycin (30 mg/kg) for the treatment of yaws. The lower dose of azithromycin is commonly used for trachoma elimination and, since yaws and trachoma are co-endemic in several regions,2Solomon AW Marks M Martin DL et al.Trachoma and yaws: common ground?.PLoS Negl Trop Dis. 2015; 9: e0004071Crossref PubMed Scopus (16) Google Scholar mass treatment with low-dose azithromycin could also aid yaws eradication. If a low-dose azithromycin treatment is as effective against yaws as standard-dose azithromycin, yaws eradication programmes can expect a considerable cost saving. Two geographic locations with yaws-affected populations, Ghana and Papua New Guinea, were selected to test the efficacy of two different azithromycin doses.1Marks M Mitjà O Bottomley C et al.Comparative efficacy of low-dose versus standard-dose azithromycin on patients with yaws: a randomised non-inferiority trial in Ghana and Papua New Guinea.Lancet Glob Health. 2018; (published online Feb 15.)http://dx.doi.org/10.1016/S2214-109X(18)30023-8Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar The non-inferiority of low-dose versus standard-dose azithromycin was investigated in patients with active yaws (defined as a skin lesion that was positive for Treponema pallidum ssp pertenue in PCR testing).3Chi KH Danavall D Taleo F et al.Molecular differentiation of Treponema pallidum subspecies in skin ulceration clinically suspected as yaws in Vanuatu using real-time multiplex PCR and serological methods.Am J Trop Med Hyg. 2015; 92: 134-138Crossref PubMed Scopus (42) Google Scholar However, non-inferiority of low-dose versus standard-dose azithromycin was not found in this group of patients, mostly because of the smaller than anticipated number of PCR-positive samples. PCR has several major advantages as a diagnostic approach in treponemal infections, including enabling differentiation between treponemal subspecies, identification of the major causes of genital ulcer disease, and recognition of treponemal infections in patients with no current serological response. However, several limitations of PCR have been described in diagnoses of treponemal infections, especially in diagnosis of syphilis. Because yaws and syphilis both manifest through a lesion development at the site of entry, are caused by genetically related treponemes4Čejková D Zobaníková M Chen L et al.Whole genome sequences of three Treponema pallidum ssp. pertenue strains: yaws and syphilis treponemes differ in less than 0·2% of the genome sequence.PLoS Negl Trop Dis. 2012; 6: e1471Crossref PubMed Scopus (79) Google Scholar that can evade the host's immune system, and disseminate via the bloodstream to various organs, the limitations of PCR diagnosis of syphilis can potentially be extrapolated to PCR diagnosis of yaws. A 2013 meta-analysis5Gayet-Ageron A Lautenschlager S Ninet B Perneger TV Combescure C Sensitivity, specificity and likelihood ratios of PCR in the diagnosis of syphilis: a systematic review and meta-analysis.Sex Transm Infect. 2013; 89: 251-256Crossref PubMed Scopus (70) Google Scholar of studies that used PCR to diagnose syphilis revealed a high specificity of PCR (around 95%) but a highly variable sensitivity, affected mainly by the specimen type (eg, swab of a primary lesion, whole blood sample) and syphilis stage (eg, primary, secondary, latent). Differences in selection of the gene target and the PCR technique used also affected the sensitivity of PCR diagnostics. In the study by Marks and colleagues,1Marks M Mitjà O Bottomley C et al.Comparative efficacy of low-dose versus standard-dose azithromycin on patients with yaws: a randomised non-inferiority trial in Ghana and Papua New Guinea.Lancet Glob Health. 2018; (published online Feb 15.)http://dx.doi.org/10.1016/S2214-109X(18)30023-8Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar a TaqMan-based real-time multiplex PCR was used to differentiate treponemal subspecies.3Chi KH Danavall D Taleo F et al.Molecular differentiation of Treponema pallidum subspecies in skin ulceration clinically suspected as yaws in Vanuatu using real-time multiplex PCR and serological methods.Am J Trop Med Hyg. 2015; 92: 134-138Crossref PubMed Scopus (42) Google Scholar In this approach, a diagnosis of yaws is based on detection of Tp0858, a gene encoding a predicted outer membrane protein. However, in 2017, a next-generation sequencing study6Marks M Fookes M Wagner J et al.Diagnostics for yaws eradication: insights from direct next generation sequencing of cutaneous strains of Treponema pallidum.Clin Infect Dis. 2017; (published online Oct 16.)DOI:10.1093/cid/cix892Crossref Scopus (18) Google Scholar of T pallidum ssp pertenue strains that were isolated in the Solomon Islands revealed a discrete phylogenetical clade of T pallidum ssp pertenue strains with substantial genetic differences, including differences in the Tp0858 gene. Several single nucleotide variants were found in the reverse primer binding site within the Tp0858 gene, which was the target of a PCR assay designed by Chi and colleagues,3Chi KH Danavall D Taleo F et al.Molecular differentiation of Treponema pallidum subspecies in skin ulceration clinically suspected as yaws in Vanuatu using real-time multiplex PCR and serological methods.Am J Trop Med Hyg. 2015; 92: 134-138Crossref PubMed Scopus (42) Google Scholar leading to false-negative PCR results on samples with these mutations. Because of the close vicinity of the Solomon Islands to Papua New Guinea, it is plausible that these genetically distant T pallidum ssp pertenue strains detected on the Solomon Islands are also present among the yaws-affected population in Papua New Guinea. It is therefore possible that several patients, despite having active yaws, were not identified by the PCR protocol used in the study by Marks and colleagues.1Marks M Mitjà O Bottomley C et al.Comparative efficacy of low-dose versus standard-dose azithromycin on patients with yaws: a randomised non-inferiority trial in Ghana and Papua New Guinea.Lancet Glob Health. 2018; (published online Feb 15.)http://dx.doi.org/10.1016/S2214-109X(18)30023-8Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar It is also possible that the modified qPCR assay,6Marks M Fookes M Wagner J et al.Diagnostics for yaws eradication: insights from direct next generation sequencing of cutaneous strains of Treponema pallidum.Clin Infect Dis. 2017; (published online Oct 16.)DOI:10.1093/cid/cix892Crossref Scopus (18) Google Scholar which contained two reverse primers to detect both sequence variants of Tp0858, could increase the number of PCR-positive patients. Consequently, a higher number of PCR-confirmed patients with active yaws at baseline could affect the results of the study regarding disproved non-inferiority of low-dose azithromycin for treatment of PCR-confirmed active yaws. The non-inferiority of low-dose azithromycin was, however, shown within the whole study population when analysed regardless of PCR results.1Marks M Mitjà O Bottomley C et al.Comparative efficacy of low-dose versus standard-dose azithromycin on patients with yaws: a randomised non-inferiority trial in Ghana and Papua New Guinea.Lancet Glob Health. 2018; (published online Feb 15.)http://dx.doi.org/10.1016/S2214-109X(18)30023-8Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar The beneficial effect of low-dose azithromycin, which is used for trachoma elimination, on the prevalence of yaws has already been shown in several regions, including Ghana7Ghinai R El-Duah P Chi KH et al.A cross-sectional study of “yaws” in districts of Ghana which have previously undertaken azithromycin mass drug administration for trachoma control.PLoS Negl Trop Dis. 2015; 9: e0003496Crossref PubMed Scopus (52) Google Scholar and the Solomon Islands.8Marks M Vahi V Sokana O et al.Impact of community mass treatment with azithromycin for trachoma elimination on the prevalence of yaws.PLoS Negl Trop Dis. 2015; 9: e0003988Crossref PubMed Scopus (36) Google Scholar, 9Marks M Sokana O Nachamkin E et al.Prevalence of active and latent yaws in the Solomon Islands 18 months after azithromycin mass drug administration for trachoma.PLoS Negl Trop Dis. 2016; 10: e0004927Crossref PubMed Scopus (16) Google Scholar Several rounds of mass drug administration of azithromycin for trachoma have been administered in Ghana in the past decade, which resulted in no evidence of active or latent yaws in this population.7Ghinai R El-Duah P Chi KH et al.A cross-sectional study of “yaws” in districts of Ghana which have previously undertaken azithromycin mass drug administration for trachoma control.PLoS Negl Trop Dis. 2015; 9: e0003496Crossref PubMed Scopus (52) Google Scholar This finding suggests that mass drug administration of azithromycin for trachoma also prevented the transmission of yaws.7Ghinai R El-Duah P Chi KH et al.A cross-sectional study of “yaws” in districts of Ghana which have previously undertaken azithromycin mass drug administration for trachoma control.PLoS Negl Trop Dis. 2015; 9: e0003496Crossref PubMed Scopus (52) Google Scholar The same result was shown on the Solomon Islands, where a single round of mass administration of low-dose azithromycin for trachoma led to a significant reduction of active yaws cases from 1·5% to 0% in 6 months.8Marks M Vahi V Sokana O et al.Impact of community mass treatment with azithromycin for trachoma elimination on the prevalence of yaws.PLoS Negl Trop Dis. 2015; 9: e0003988Crossref PubMed Scopus (36) Google Scholar The effect of this mass administration was even greater in patients with latent yaws, in whom the prevalence of yaws decreased from 20·2% before treatment to 3·6% after treatment.8Marks M Vahi V Sokana O et al.Impact of community mass treatment with azithromycin for trachoma elimination on the prevalence of yaws.PLoS Negl Trop Dis. 2015; 9: e0003988Crossref PubMed Scopus (36) Google Scholar After 18 months, the beneficial effects of low-dose azithromycin on the prevalence of yaws on the Solomon Islands was maintained without any further interventions.9Marks M Sokana O Nachamkin E et al.Prevalence of active and latent yaws in the Solomon Islands 18 months after azithromycin mass drug administration for trachoma.PLoS Negl Trop Dis. 2016; 10: e0004927Crossref PubMed Scopus (16) Google Scholar Therefore, although the trial by Marks and colleagues did not show the non-inferiority of low-dose azithromycin to the standard dose in PCR-confirmed active yaws, epidemiological evidence would suggest that both seem to be equally effective against yaws infections. We declare no competing interests. Comparative efficacy of low-dose versus standard-dose azithromycin for patients with yaws: a randomised non-inferiority trial in Ghana and Papua New GuineaIn this study, low-dose azithromycin did not meet the prespecified non-inferiority margin compared with standard-dose azithromycin in achieving clinical and serological cure in PCR-confirmed active yaws. Only a single participant (with presumed latent yaws) had definitive serological failure. This work suggests that 20 mg/kg of azithromycin is probably effective against yaws, but further data are needed. Full-Text PDF Open Access