Background

Yaws is a relapsing non-venereal treponematosis caused by Treponema pallidum subspecies pertenue. The disease mainly affects the skin, but if untreated, can also affect bone, joints and cartilage. Yaws may persist for many years as a chronic infection, and late stage disease may lead to crippling disfigurement [1, 2]. The bacterium that causes yaws is closely related to T. pallidum ssp. pallidum, the causative organism of venereal syphilis, however T. pallidum ssp. pertenue is thought to be less virulent [3]. Transmission of yaws occurs from person to person through direct skin to skin contact, involving transfer of infectious exudates from the early skin lesions of infected individuals to micro- or macro-abrasions of the skin of siblings/playmates. [4–7].

Yaws was previously widespread throughout the tropics but a global eradication campaign between 1952 and 1964 resulted in a 95% reduction in disease prevalence worldwide [8]. Following this initial success, yaws control was integrated into national primary healthcare systems. Unfortunately, this integration resulted in a weakening of yaws surveillance in many countries and the re-emergence of the disease by the 1970s [9]. Several reports have recently documented a resurgence of yaws in parts of West and Central Africa, South East Asia and several Western Pacific Islands [10–12]. Yaws is an important public health problem in Ghana and affects the poor rural communities. The disease is reported in all the ten regions of the country. A prevalence study in three purposively selected districts in Southern Ghana in 2008 showed an overall prevalence of 1.92% among children in primary schools; however individual school prevalence rates ranged from 0% to a high of 19.5% [13].

Previous mass treatment campaigns to eradicate yaws in Ghana were based on the use of a single dose intramuscular (IM) injection of long-acting penicillin. The advantages of single-dose treatment with penicillin are its low cost, adherence and the absence of antimicrobial resistance despite extensive use. However, treatment with intramuscular penicillin has several disadvantages such as pain, anaphylaxis, and potential for transmission of other blood-borne infections.

Azithromycin has previously been shown to be an effective agent in the treatment of venereal syphilis [14]and is also the cornerstone of the strategy for the elimination of trachoma [15]. Azithromycin offers a number of advantages as an agent for the treatment of yaws, including its low cost, oral route of administration, excellent safety profile and negligible risk of anaphylaxis. As such, the drug is well suited for use in community mass treatment campaigns for yaws eradication [16]. In 2012, a single centre study conducted in Papua New Guinea, showed that a single oral dose of 30mg/kg azithromycin was non-inferior to a single injection of benzathine penicillin in the treatment of the disease, Clinical cure rate was 85.4% (95% CI: 78.2–90.6) in patients treated with azithromycin compared to 86.5% (95% CI: 79.5–91.5) in those treated with benzathine penicillin [17]. These findings led to recommendations incorporated into the WHO’s Morges yaws eradication strategy [18]. Here, we report a similar study carried out in Ghana, West Africa in order to confirm the efficacy and suitability of azithromycin for treatment of yaws in Sub-Saharan Africa.

Ethics Statement

This trial was conducted according to the principles of the Declaration of Helsinki. The study was approved by the Ghana Health Service Ethical Review Committee (Ref: GHS-ERC: 13/11/10). Written informed consent was obtained from parents/guardians of all participants; those aged 12 years and above also signed an assent certificate.

Study Setting

The study was conducted between 25^th May 2011 and 31^st December 2012 in three neighbouring yaws endemic districts in southern Ghana: Ga South, Awutu Senya and West Akim districts (Fig 1). The three study districts have a total population of 787,747 with a distribution of 316,091, 274,584 and 197, 072 respectively. Children under the age of 15 years, known to bear the bulk of yaws infections, represent an estimated 38.3% of these populations. There are more than 600 rural communities in these three districts. The districts have a total of 8 government and private hospitals, 10 government health centres, 81 private health facilities made up of small clinics and maternity homes and 16 Community Based Health Planning and Services (CHPS) compounds. Only 20% of these health facilities are located in the rural parts of the district where yaws occurs. The doctor population ratio in the study area is 1:15,754.

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Fig 1. Study Districts Ga South, Awutu Senya and West Akim Districts of Ghana.

In 2012 the Awutu Senya district was divided into Awutu Senya and Awutu Senya East districts.

https://doi.org/10.1371/journal.pntd.0005154.g001

The main occupation of the people in the study area is subsistence farming. There are a total of 1750 primary schools and kindergartens in the study area with a total enrollment of 174, 536 made up of 51% males and 49% females.

Yaws surveillance in the study area is mainly by passive detection at the health facilities. Based on routine reports of presentation of clinical cases to health facilities and a small number of active case searches in schools, the yaws case notification rate has been estimated to be between 87–241 per 100,000 people. Between 2009 and 2011, 2674 clinical cases of yaws were reported in the 3 study districts combined.

Study Participants

Participants were recruited based on clinical suspicion by health workers at home or in school, and all subjects with suspected yaws were assessed for eligibility. Clinical examination involved inspection of the skin and scalp for signs of early yaws lesions. A suspected case of primary yaws was defined as an ulcer with raised edges and a dirty crusty base or a papilloma that appeared as a firm yellowish skin lesion with a dark tip, on any part of the body. A suspected case of secondary yaws was defined as any of the following skin lesions: multiple ulcerative or papillomatous skin lesions; a palmar or plantar hyperkeratosis or a macular, papular or maculopapular skin lesion. A confirmed case of yaws was defined as a suspected case with a positive TPHA test and an RPR titre of at least 1:4.

Photographs of the lesions were taken before treatment and subsequently at follow-up review visits. A 5mL sample of venous blood was collected from those with lesions clinically suggestive of yaws and analyzed at the National Public Health Reference Laboratory in Accra by qualitative Treponema pallidum haemaglutination assay (TPHA) testing (Debens Diagnostics Ltd., Ipswich, UK.). In parallel, a second set of frozen sera were sent to the Komfo Anokye Teaching Hospital serology laboratory in Kumasi for qualitative and quantitative rapid plasma reagin (RPR) testing (Immutrep RPR test kit, Omega Diagnostics, Alva UK).

Inclusion criteria for enrolment were individuals aged 1–15 years with suspected primary or secondary yaws, a reactive TPHA test and a RPR titre of at least 1:4. Exclusion criteria were a negative qualitative TPHA test, a baseline RPR titre of less than 1:4, allergy to penicillin and/or a macrolide antibiotic, a medical condition that would impair drug absorption, recent ingestion of a broad spectrum antibiotic (30 days prior to the day of randomisation) and patients who were not willing to give informed consent or who would not be available for follow up visits.

Study Drugs

In this study azithromycin manufactured by Pfizer in the strength of 250mg tablets was supplied by Gokals Laborex, Ghana. Benzathine penicillin, 1.2 million units per vial, manufactured by Troge Medicals, Hamburg was supplied by Ghana Health Service Central Medical Stores.

Randomisation Process

Participants who met the inclusion criteria were randomized to receive treatment with either a single dose oral azithromycin administered at a dose of 30mg/kg (maximum of 2g) or a single dose of benzathine penicillin administered as an intramuscular injection of 1.2 million units for subjects 10-15years, and 0.6 million units for those below 10 years of age. Participants in both arms were directly observed receiving treatment and for two hours thereafter.

The allocation sequence was based on a computer generated block randomization scheme, stratified according to district. Participants were allocated in a ratio of 1:1 to treatment with azithromycin or penicillin. Treatment allocation was concealed from investigators through the use of sequentially numbered, opaque, sealed envelopes that were kept in a safe and were opened at the point of treatment by the treatment team.

Owing to the obvious differences between the mode of administration of the two drugs, investigators and study participants could not be blinded to the treatment received, however individuals assessing study outcomes were masked to treatment allocation.

Serological tests were conducted in separate laboratories by laboratory technicians masked to clinical data.

Follow—Up

Participants were followed up at 3 weeks, 3 months and 6 months. Skin lesions were re-examined at 3 weeks post treatment. At 3 months and 6 months, skin lesions were examined and blood collected for repeat quantitative RPR testing. Individuals with lesions that had not healed at follow-up were re-treated with benzathine penicillin. Health workers and community-based surveillance volunteers monitored and documented all adverse events up to 72 hours after treatment. Parents and teachers also were counselled on possible adverse events after the field team had departed and the need to report to the nearest health facility if necessary. Adverse events that occurred within 2 hours of treatment were documented and managed by the field teams.

Our primary outcome was clinical cure defined as a total or partial resolution of yaws skin lesions 3 weeks after treatment. The secondary outcome was serological cure defined as at least a 4-fold drop in baseline RPR titre within 6 months of treatment. Treatment was considered to have failed if there was no resolution of yaws skin lesions (complete or partial) 3 weeks after treatment.

Statistical Analysis

This trial was designed to assess if azithromycin was non-inferior to benzathine penicillin for the treatment of yaws. With an expected efficacy of penicillin of 95%, a type 1 error of 0.05, and a non-inferiority margin of 10% and assuming that 10% would be lost to follow-up, a sample size of 310 children (155 per arm) would give a statistical power of 90% to test the hypothesis. Analysis of the primary endpoint of clinical cure was estimated by the two-sided 95% confidence interval for the difference in cure rates between the penicillin and azithromycin groups. Secondary outcome analyses were done using similar methods. Subgroup analyses were performed with stratification by baseline RPR titre, household exposure to yaws and stage of clinical yaws. A two-sided test at a significance level of 0.05 was used in the comparison of baseline characteristics of the two treatment groups. All statistical analyses for this study were carried out in STATA 11.1 (Statacorp, Texas, USA). The per-protocol (PP) analysis included all subjects who completed all study procedures at 6 months. The intention-to-treat (ITT) analysis included all eligible participants who were randomised and treated. Individuals with missing data were considered treatment failures for the purposes of the intention-to-treat analysis.