A Single Dose Oral Azithromycin versus Intramuscular Benzathine Benzylpenicillin for the Treatment of Yaws- A Randomised Non Inferiority Trial in Ghana

Abstract

Background: Yaws is a treponemal infection that was almost eradicated fifty years ago has re-emerged in a number of countries including Ghana. Single dose intramuscular benzathine benzylpenicillin was the recommended treatment. However treatment by intramuscular injection poses several operational and logistical constraints in poor communities where yaws occurs. Results of a randomized clinical trial in Tanzania showed that azithromycin was effective against syphilis a venereal treponemal infection, however little is known about its effect on yaws. This study describes the epidemiological characteristics of yaws including its prevalence and risk factors, and compares the efficacy of a single dose oral azithromycin as an alternative to intramuscular benzathine benzylpenicillin for the treatment of yaws in three selected yaws endemic districts in Southern Ghana namely: Awutu Senya, Ga South and West Akim districts. Methods: To describe the epidemiology of yaws we conducted a cross sectional survey that described the prevalence of the disease among various socio-demographic groups in the study area, and a case control study to determine various risk factors associated with the disease. In the clinical trial we set out to test the hypothesis that azithromycin was inferior to injection benzathine benzylpenicillin by 10% in the treatment of yaws. We conducted an open-label, randomized non-inferiority trial in the three selected yaws endemic districts. Children aged 1-15 with yaws lesions were assigned to receive either 30mg/kg of oral azithromycin or benzathine benzylpenicillin at a dosage of 0.6 million units for children below 10 years and 1.2 million units for those 10 years and above. The primary end point was clinical cure rate, defined as a complete or partial resolution of lesions 3 weeks after treatment. The secondary endpoint was serological cure, defined as at least a four-fold decline in baseline RPR titre 6 months after treatment. Non- inferiority of azithromycin was determined if the upper bound limit of a 2 sided 95% CI was less than 10%. The trial was registered with Pan African Clinical Trials Registry number PACTR 2013030005181. Results: The overall prevalence of yaws in the study area was 1.95%; however district prevalence ranged from 0.96% in the West Akim district to 2.77% in the Awutu Senya district. Yaws prevalence among female participants was 1.76% compared to 2.05% among male participants. Participants below 5 years had the lowest prevalence of 1.77%; the age group with the highest prevalence of 2.02% was 11-15 years. Results of the univariate analysis showed several risk factors associated with yaws: Males were 1.8 times more likely to have yaws compared to females (OR: 1.8, CI: 1.0-3.2, p-value=0.032). Persons who do not bath daily were 3 times more likely to have yaws compared to those who bathed daily, (OR=3.0, CI: 1. 0-5.4, p-value=0.000). The results also showed that persons living in a compound house were 1.8 times more likely to have the disease compared to those who lived in single houses ( OR=1.8, CI: 1. 0-3.4, p-value=0.048). Persons sleeping in a bedroom with more than 7 occupants were 4.4 times more likely to get yaws than those sleeping in a room with fewer people (OR= 4.4, CI: 1.4-16.8, p-value =0.004). However in the multivariate analysis the risk factors with significant association with yaws were living in a compound house (OR= 2.0, CI 1.0 – 3.8, p-value=0.047) and not bathing daily (OR= 2.4, CI: 1.3-4.4, p value=0.005). The mean age of trial participants was 9.5 years (S.D.3.1, range 1-15 years), 247(70%) were males. The clinical cure rates were 98.2 % in the azithromycin group and 96.9 % in the penicillin group (risk difference:-1.3%,(-4.7 to 2.0). The serological cure rates at 6 months were 57.4% in the azithromycin group and 49.1 % in the penicillin group (risk difference:-8.3%,(-19.1 to 2.4), achieving the specified criteria for non-inferiority. Conclusion: Conclusion: Yaws was shown to be still present in some rural communities in Ghana; risk factors are related to hygiene and overcrowding. A single oral dose of azithromycin, at a dosage of 30mg/kg, is non inferior to intramuscular benzathine benzylpenicillin for the treatment of early yaws hence the hypothesis of inferiority of azithromycin compared to penicillin is rejected. This finding is particularly useful in developing countries in removing the requirement for trained health personnel required to administer treatment by intramuscular injection during mass campaigns.