Three-round strategy bests targeted treatment in reducing community caseload

Three rounds of mass community administration of azithromycin proved more effective at reducing the prevalence of yaws than a single round of mass dosing followed by targeted treatment, according to findings from an open-label, cluster-randomized, community-based trial from Papua New Guinea.

Yaws is a chronic infection—caused by Treponema pallidum subspecies pertenue and characterized by papillomas and ulcers—which affects the skin and bones of children in poor, rural communities in tropical regions, explained Lucy N. John, MD, of the National Department of Health in Aopi Center, the School of Medicine and Health at the University of Papua New Guinea, and the Hospital Universitari Germans Trias i Pujol and University of Barcelona in Barcelona, Spain, and colleagues in The New England Journal of Medicine.

Following the finding that a single dose of azithromycin is just as effective as penicillin G benzathine in treating yaws infection, the World Health Organization launched a worldwide program to eradicate the condition by 2030. Currently, that program primarily consists of a single round of mass azithromycin administration, irrespective of infection status, followed by targeted treatment of active cases and case contacts every 6 months. However, previous research conducted in Papua New Guinea suggests that this strategy misses patients with latent infections.

“On the basis of both empirical and modeling data, we hypothesized that three rounds of mass administration of azithromycin before switching to targeted treatment would be more effective in reducing the prevalence of active and latent yaws than standard care with one round of mass administration of azithromycin,” John and colleagues wrote.

For their community-based trial, these researchers assigned patients to receive either three rounds of mass community azithromycin administration (experimental group) or one round of community administration followed by two rounds of targeted treatment. The study authors randomly assigned 38 “wards”—the smallest local administrative unit, consisting of three to five villages sharing the same school, church, or both—from the Matalai Rural, Namatanai Rural, and Sentral Niu Ailan Rural areas of Papua New Guinea’s Namatanai District. All individuals older than 1 month and living in the trial wards were eligible to participate.

Thirty-eight field teams were responsible for screening residents and delivering treatment—study visits occurred at baseline, 6 months, and 12 months. The control group (19 wards; 30,438 residents) received one round of mass administration followed by rounds of targeted treatment at 6 and 12 months, while the experimental group (19 wards; 26,238 residents) received three rounds of mass azithromycin. The antibiotic was administered orally as a single dose, with dosage adjusted by age (four 500-mg tablets for patients 15 years and older; three tablets for patients ages 10-14; two tablets for patients ages 5-9; one tablet or 7.5 ml of azithromycin syrup for patients ages 1-4; and 5 ml azithromycin syrup for ages 1-12 months).

The study’s coprimary endpoints were prevalence of active yaws cases—confirmed via polymerase-chain-reaction (PCR) assay—in the entire population and the prevalence of latent yaws—confirmed by serologic testing—in a subgroup of asymptomatic children ages 1-15. Prevalence of active and latent cases were measured at 18 months to calculate between-group differences. The field teams also sequenced samples to assess the presence of “the point mutations A2058G and A2059G in the 23S ribosomal RNA (rRNA) genes causing macrolide resistance…”

The field teams administered a total of 24,848 doses of azithromycin in the control group (22,033 at round one; 207 and 2,608 given to individuals with yaws-like lesions and contacts at rounds two and three, respectively) and 59,852 doses in the experimental group.

“At 18 months, the prevalence of active yaws had decreased from 0.46% (102 of 22,033 persons) at baseline to 0.16% (47 of 29,954 persons) in the control group and from 0.43% (87 of 20,331 persons) at baseline to 0.04% (10 of 25,987 persons) in the experimental group (relative risk adjusted for clustering, 4.08; 95% confidence interval [CI], 1.90 to 8.76),” John and colleagues found. “The prevalence of other infectious ulcers decreased to a similar extent in the two treatment groups.”

They also found that, at 18 months, the prevalence of positive serologic tests for latent yaws was 6.54% (95% CI, 5.00-8.08) among a subgroup of 994 children in the control group and 3.28% (95% CI, 2.14-4.42) among 945 children in the experimental group.

“All the cases of yaws had a wild-type 23S rRNA, except for three cases at the 18-month survey in the experimental group, which had the A2058G mutation associated with macrolide resistance,” they added.

This last point may help to explain why, despite a substantial reduction in prevalence with a three-round mass dosing strategy, yaws was not eliminated in the study population—the frequency of resistance seen in this study “was similar to what we observed after repeated targeted-treatment rounds in the nearby island of Lihir,” they noted. They concluded that this finding highlights “the need to maintain careful clinical and molecular surveillance for the emergence of antimicrobial resistance in T. pallidum subspecies pertenue and other bacterial organisms associated with mass drug administration.

Another possible explanation for the failure to eliminate yaws is “a spillover of cases from the wards in the control group to the wards in the experimental group, an insufficient number of latent cases treated, or active cases that were missed,” they added. “An assessment of this outcome is difficult because we did not have longitudinal information at the individual level for the whole population.”

Study limitations included a lack of an updated population census, an inability to determine whether a different number of rounds of mass drug administration might have been more effective, and a lack of assessment for emergence of macrolide resistance in other organisms.

  1. Three rounds of mass community dosing with azythromycin, irrespective of infection, was more effective at reducing yaws prevalence compared to the current strategy of one round of mass community dosing followed by targeted treatment of active cases and contacts, according to a study from Papua New Guinea.
  2. The presence of antimicrobial resistance among three individuals in the experimental group highlights the need to maintain careful clinical and molecular surveillance for the emergence of antimicrobial resistance in T. pallidum subspecies pertenue and other bacterial organisms associated with mass drug administration.

John McKenna, Associate Editor, BreakingMED™

This study was supported by Fundació “la Caixa,” Diputació de Barcelona, and Fundació Barberà Solidària. The Papua New Guinea National Department of Health provided logistic and personnel support and disseminated information to raise awareness in communities and among local stakeholders.

Azithromycin was donated by Kern Pharma and was provided at no cost to the trial participants.

John had no relevant relationships to disclose.


Cat ID: 190

Topic ID: 79,190,287,585,730,190,192,925