Keenan JD, Emerson PM, Gaynor BD, Porco TC, Lietman TM. Adult Mortality in a Randomized Trial of Mass Azithromycin for Trachoma. JAMA Intern Med. 2013;173(9):821-823. doi:10.1001/jamainternmed.2013.3041
Author Affiliations: Francis I. Proctor Foundation (Drs Keenan, Gaynor, Porco, and Lietman), Department of Ophthalmology (Drs Keenan, Gaynor, Porco, and Lietman), Department of Epidemiology and Biostatistics (Drs Porco and Lietman), and Institute for Global Health (Dr Lietman), University of California, San Francisco; and the Carter Center, Atlanta, Georgia (Dr Emerson).
Annual mass azithromycin treatments are provided to entire communities to clear the ocular strains of Chlamydiatrachomatis that cause blinding trachoma. Mass treatments reduce the community burden of ocular chlamydia and have proven efficacious in community-randomized trials.1 Since 1999, more than 150 million doses of azithromycin have been distributed for trachoma worldwide.2
Mass azithromycin distributions are directed at clearing ocular chlamydia but may have other effects. For example, in the Trachoma Amelioration in Northern Amhara (TANA) trial, we found that mass azithromycin distributions reduced childhood mortality.3 In contrast, a recent observational study suggested that azithromycin use may cause sudden death in adults.4 This finding could have major implications for trachoma elimination efforts. In our previous report, an intention-to-treat analysis found no evidence of increased mortality among individuals older than 9 years.3 However, in light of the recent observational study, we thought it worthwhile to reassess our data to determine the mortality rates and causes of death in an older subgroup of individuals and to compare mortality in individuals who received azithromycin with that in those who did not.
TANA was a National Institutes of Health–funded, cluster-randomized trial conducted in Ethiopia from 2006 through 2009 (clinicaltrials.gov Identifier: NCT00322972). The design and implementation of the trial, including the prespecified mortality outcome, have been described previously.3 Herein we report results from the following 4 study arms, each composed of 12 randomly selected “subkebeles” (government-defined units): (A) annual or (B) biannual directly observed mass distribution of azithromycin to persons 1 year or older, (C) quarterly mass distribution of azithromycin to children aged 1 to 9 years, and (D) no treatment. Mortality was defined as presence at the baseline census and absence at the 12-month census due to death. For each death, household members were asked about the cause of death.
In an intention-to-treat analysis, we compared communities where individuals aged at least 10 years received azithromycin (arms A and B) with communities where this age group did not receive treatment (arms Cand D). We used negative binomial regression to calculate age-stratified mortality rates and mixed effects logistic regression to compare the 2 groups, with subkebele as a random effect. As a second independent analysis, we treated arms A and B as a cohort and compared mortality in persons who received any dose(s) of azithromycin relative to those who received no doses. This analysis could be biased if the baseline health status differed between participants and nonparticipants.5 Therefore, we performed a conditional logistic regression grouped on household, which removes all household-level confounding. We included sex and the interaction of age stratum by antibiotic treatment to account for individual-level confounding, and we report the odds ratio for the 30-years-and-older group. The TANA trial provided 80% power to detect a 0.7% reduction in the mortality rate of participants aged at least 30 years, assuming a mortality rate of 10 per 1000 person-years, 350 persons aged at least 30 years per subkebele, and a variance inflation factor of 2. Statistical analyses were performed with Stata software, version 10.1 (StataCorp).
Ethical approval for this study was obtained from the University of California, San Francisco Committee for Human Research, the Emory University Institutional Review Board, and the Ethiopian Science and Technology Commission.
Baseline characteristics of the 4 treatment groups were similar (reported elsewhere).3 Of 8217 persons aged at least 30 years who were present at baseline in arms A and B, 7252 (88.3%) received azithromycin during the year. Of 8320 persons aged at least 30 years who were present at baseline in arms C and D, 109 (1.3%) mistakenly received azithromycin. By the 12-month census, 166 individuals aged 30 years or older had died. Although we were unable to detect a significant difference, mortality was lower in arms A and B than in arms C and D (odds ratio, 0.91 [95% CI, 0.63-1.30]). Causes of death were similar in the 2 groups (Table).
A separate analysis of arms A and B found no difference in mortality between individuals aged at least 30 years who received azithromycin and those who did not, although those who received azithromycin had a lower risk of mortality than did members of the same household who never received the drug (adjusted odds ratio, 0.59 [95% CI, 0.17-2.00], conditional logistic regression).
We were unable to detect an association between azithromycin use and increased risk of all-cause or cause-specific mortality among adults in this study; to the contrary, individuals treated with azithromycin had a lower rate of mortality compared with those who did not receive treatment. This lack of an association is in contradiction to a previous report that found an increased risk of sudden death in patients treated with azithromycin.4 The 2 studies are clearly different. Ours was a randomized clinical trial of healthy adults in Ethiopia, whereas theirs was a propensity score–adjusted observational study of hospitalized patients in Tennessee. Other studies have demonstrated that mass azithromycin distributions for trachoma have collateral benefits (eg, decrease in childhood respiratory infections, diarrhea, malaria, and mortality) and potential harms (eg, transient macrolide resistance).3,6- 8 An argument could be made for trachoma programs to stop distributing azithromycin to adults, especially since the greatest burden of ocular chlamydia is found in children, and treatment of children provides some degree of indirect herd protection for adults.9 However, our findings provide no evidence to support discontinuation of mass distributions to entire communities for trachoma control, suggesting that if anything, benefit outweighs harm.
Correspondence: Dr Keenan, Box 0412, 513 Parnassus Ave, Med Sci S334, University of California, San Francisco, San Francisco, CA 94143-0412 (firstname.lastname@example.org).
Published Online: April 1, 2013. doi:10.1001/jamainternmed.2013.3041
Author Contributions: Drs Keenan and Lietman had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Emerson, Gaynor, and Lietman. Acquisition of data: Lietman. Analysis and interpretation of data: Keenan, Emerson, Porco, and Lietman. Drafting of the manuscript: Keenan. Critical revision of the manuscript for important intellectual content: Emerson, Gaynor, Porco, and Lietman. Statistical analysis: Keenan and Porco. Obtained funding: Emerson and Lietman. Administrative, technical, and material support: Emerson and Gaynor. Study supervision: Lietman.
Conflict of Interest Disclosures: None reported.
Funding/Support: The National Eye Institute of the National Institutes of Health was the primary supporter of this study (grant U10 EY016214) and also provided support for Dr Keenan (grant K23 EY019071). Pfizer International (New York, New York) and the International Trachoma Initiative provided the azithromycin. Donations were also provided by the Bernard Osher Foundation, That Man May See, the Peierls Foundation, the Bodri Foundation, the Harper Inglis Trust, the South Asia Research Fund, and Research to Prevent Blindness.
Role of the Sponsors: The study funders had no role in the study design, implementation, analysis, manuscript preparation, or decision to submit this article for publication.
Additional Contributions: Donald Everett, MA (National Eye Institute, Bethesda, Maryland) was the program officer for the clinical trial. The data safety and monitoring committee included William Barlow, PhD (University of Washington, Seattle; chair), Donald Everett, MA (National Eye Institute, Bethesda, Maryland), Larry Schwab, MD (International Eye Foundation, Kensington, Maryland), Arthur Reingold, MD (University of California, Berkeley), and Serge Resnikoff, MD (Brien Holden Vision Institute, Sydney, Australia; and International Health and Development, Geneva, Switzerland). These individuals received reimbursement for the expenses associated with their work on this article but otherwise did not receive compensation. The Goncha woreda health office, the Amhara Regional Health Bureau, and the Ethiopian Ministry of Health allowed and organized health workers to be employed by the study as data collectors.