Feasibility of Eliminating Ocular Chlamydia Trachomatis with Repeat Mass Antibiotic Treatments

BRIEF REPORT

Feasibility of Eliminating Ocular Chlamydia trachomatis With Repeat Mass Antibiotic Treatments

Muluken Melese, MD, MPH Context Mass antibiotic administrations for ocular chlamydial infection play a key Jaya Devi Chidambaram, MBBS role in the World Health Organization’s trachoma control program. Mathematical mod- Wondu Alemayehu, MD, MPH els suggest that it is possible to eliminate trachoma locally with repeat mass treatment, depending on the coverage level of the population, frequency of mass treat- David Chung Lee, BSc ments, and rate that infection returns into a community after each mass treatment. Elizabeth H. Yi Precise estimates of this latter parameter have never been reported. Vicky Cevallos, BSc Objective To determine the rate at which chlamydial infection returns to a population after mass treatment and to estimate the treatment frequency required for elimi- Zhaoxia Zhou nation of ocular chlamydia from a community. Cathy Donnellan Design, Setting, and Participants Longitudinal cohort study of 24 randomly se- Michael Saidel, MD lected villages from the Gurage Zone in Ethiopia conducted February 2003 to Octo- ber 2003. A total of 1332 children aged 1 to 5 years were monitored for prevalence of John P. Whitcher, MD, MPH ocular chlamydial infection pretreatment and 2 and 6 months posttreatment. Bruce D. Gaynor, MD Interventions All individuals older than 1 year were eligible for single-dose oral azithro- Thomas M. Lietman, MD mycin treatment. Pregnant women were offered tetracycline eye ointment. Main Outcome Measures Prevalence of ocular chlamydial infection, measured by ASS ANTIMICROBIAL AD- polymerase chain reaction, in children aged 1 to 5 years, in each of 24 villages at each ministrations have been time point was used to estimate the rate of return of infection and the treatment fre- used in several control quency necessary for elimination. programs and have been Results The prevalence of infection was 56.3% pretreatment (95% confidence contemplatedM for many others. They interval [CI], 47.5%-65.1%), 6.7% 2 months posttreatment (95% CI, have proven to be effective against some 4.2%-9.2%), and 11.0% 6 months posttreatment (95% CI, 7.3%-14.7%). Infec- parasitic diseases (eg, onchocerciasis and tion returned after treatment at an exponential rate of 12.3% per month (95% CI, 4.6%-19.9% per month). The minimum treatment frequency necessary for elimina- filariasis), but at times have not lived up 1-3 tion was calculated to be once every 11.6 months (95% CI, 7.2-30.9 months), to expectations (eg, malaria). Vari- given a coverage level of 80%. Thus, biannual treatment, already being performed ous forms of mass treatment have been in some areas, was estimated to be more than frequent enough to eventually elimi- used for bacterial diseases, including nate infection. sexually transmitted chlamydia and Conclusion The rate at which ocular chlamydial infection returns to a community 4,5 syphilis. The World Health Organiza- after mass treatment suggests that elimination of infection in a hyperendemic area 6 tion (WHO) and its partners are now is feasible with biannual mass antibiotic administrations and attainable coverage using repeated mass azithromycin ad- levels. ministrations to control the ocular JAMA. 2004;292:721-725 www.jama.com strains of chlamydia that cause trachoma, the world’s leading cause of in- Author Affiliations: ORBIS International, Addis and Lietman), Institute for Global Health (Drs fectious blindness.7 Trachoma meets the Ababa, Ethiopia (Drs Melese and Alemayehu); WHO Whitcher and Lietman), University of California, San Collaborating Center, F.I. Proctor Foundation Francisco. critical criteria for eradicability: there is (Drs Chidambaram, Saidel, Whitcher, Gaynor, and Corresponding Author: Thomas M. Lietman, MD, an effective treatment for the ocular Lietman, Mr Lee, and Mss Yi, Cevallos, Zhou, and WHO Collaborating Center, F.I. Proctor Foundation, Donnellan), Department of Ophthalmology Room 307, 95 Kirkham St, University of California, strains of Chlamydia trachomatis, and (Drs Gaynor, Whitcher, and Lietman), Department San Francisco, San Francisco, CA 94143-0944 there is no known animal reservoir. Cur- of Epidemiology and Biostatistics (Drs Whitcher ([email protected]).

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all members of the community except Figure 1. Map of Gurage Zone of Ethiopia Displaying Villages Randomly Selected for the Study children younger than 1 year. Chil- dren younger than 1 year were ex- ERITREA cluded because azithromycin was ap- SUDAN YEMEN proved for use in Ethiopia only for Zone Borders DJIBOUTI children 1 year and older. Adherence ETHIOPIA Woreda Borders Selected Villages (24) to therapy was essentially 100% of those WEST SHEWA ZONE Note: Distances Are Approximate treated, since administration of the Gurage Zone single-dose antibiotic was directly ob- SOMALIA served. Pregnant women were offered KENYA topical tetracycline ointment. Guard- Sodo Kebena ians were asked to bring all children Abeshge Kokir Gedabano aged 1 to 5 years, the ages most likely

Muher Aklil to harbor infection, to a central loca- tion in their village for examinations at JIMMA Cheha GURAGE ZONE baseline and 2 and 6 months after treat- ZONE Meskan Eja ment (±1 week, from March 2003 to N October 2003). Verbal consent was ob- Enemor tained from the parent or guardian of Mareko Gumer each child. The right upper tarsal conjunctiva of each child was everted and YEM Endegagne SILTI ZONE ZONE swabbed. Swabs were placed immedi- HADIYA ZONE EAST SHEWA ately at 4°C and at −20°C within 6 ZONE hours, and transported at 4° C to the University of California, San Fran- cisco for processing with the Ampli- rently, there is little evidence of emerg- fection returns to a community after cor polymerase chain reaction (PCR) ing chlamydial resistance to macro- mass treatment,11 but precise esti- test (Roche Molecular Systems, Branch- lides;8 however, susceptibility testing in mates of the important latter param- burg, NJ) according to protocol. chlamydia is difficult to measure and eter have never been reported. Here we Posttreatment samples from the same rarely performed, and further surveil- determine the rate at which chla- village were pooled by random selec- lance may be needed.9 Trachoma has al- mydial infection returns to a hyperen- tion into groups of 5, and 200 µL of ready disappeared from most devel- demic population in Ethiopia, and from each of the 5 samples was pooled into oped countries—the last documented this we estimate the treatment cover- a single tube for processing.12-14 The case of indigenous active trachoma in the age and frequency (ie, biannual, an- prevalence in each village was then es- United States appears to have been in the nual) required to eliminate infection. timated from the proportion of posi- 1970s.10 Nevertheless, the general con- That is, we determine whether elimi- tive pools, using maximum likelihood sensus among public health workers is nation of ocular chlamydia from se- estimation as previously described.15 that the incidence of ocular chlamydial verely affected areas is a feasible goal. Laboratory controls were included ac- infection cannot be reduced to zero in cording to the Roche Amplicor proto- the most hyperendemic areas with an- METHODS col. In addition, negative field controls tibiotics alone. A geographical area was selected from were obtained from at least 5 random Can trachoma infection be elimi- the Gurage Zone of Ethiopia that in- children from each village. Immedi- nated from the most hyperendemic cluded 3 subdistricts and about 112000 ately after the study swab and before areas with repeated mass antibiotic ad- people (FIGURE 1). A stratified sample changing gloves for the next patient, a ministrations? Mathematical models re- of 24 villages was randomly chosen second swab was passed within 1 inch veal that it is theoretically possible to from a complete list of all villages (8 of the conjunctiva without touching. eliminate infection locally even with- from each of the 3 subdistricts). A cen- These control swabs were processed in out complete antibiotic coverage by sus was conducted (February and a manner identical to the study swabs; progressively reducing the prevalence March 2003), and all village residents if a pooled control was found to be posi- of infection with each treatment.11 aged 1 year and older were eligible to tive, then all samples in that pool were Elimination is dependent on the effi- participate in the study. A single oral individually retested. All specimens were cacy of the antibiotic in an individual, dose of azithromycin (1 g to adults, 20 processed in a masked manner. the coverage and frequency of treat- mg/kg to children) was offered within The rate of return of infection after ment, and the initial rate at which in- 2 weeks of the baseline examination to treatment was determined from the ob-

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served increase in prevalence from 2 to Table. Antibiotic Coverage, Study Participation, and Prevalence of Ocular Chlamydia by 6 months after treatment. Using this rate, Village in Gurage Zone, Ethiopia the treatment frequency necessary to Baseline 2mo 6mo achieve elimination was obtained from Pretreatment Posttreatment Posttreatment the following inequality11: No. of villages sampled* 24 24 24 Total No. of children aged 1 to 5 y examined 1332 1316 1321 1 Estimates, mean % (95% CI)† Ͼe(rate ϫ period) 1−(coverage ϫ efficacy) Village treatment coverage 91.9 (89.3-94.5) Monitor only Monitor only Village PCR participation 91.1 (88.7-93.5) 91.5 (88.7-94.3) 90.1 (87.6-92.6) where efficacy is the efficacy of the an- Village prevalence by PCR 56.3 (47.5-65.1) 6.7 (4.2-9.2) 11.0 (7.3-14.7) tibiotic in an individual, and period is the Prevalence, No. of villages Ͼ50% 14 0 0 duration between treatments. The left- Ͼ20% to Յ50% 10 0 4 hand side of the inequality represents Ͼ0% to Յ20% 0 18 14 how much a single mass treatment with 0% 066 a given antibiotic efficacy and coverage Abbreviations: CI, confidence interval; PCR, polymerase chain reaction. reduces the level of infection at each *The same 24 villages were sampled at each time point. treatment. The right-hand side repre- †Coverage, participation, and prevalence estimates were calculated at the village level. Means and 95% CIs reflect this. sents the exponential increase of infection during the period between treat- All research was conducted in accor- ous strata in the Table. After mass treatments. For eventual elimination, the dance with the Declaration of Helsinki. ment, the exponential rate of return of fraction of infection reduced by each We obtained ethical approval from the infection was calculated to be 12.3% per treatment must be greater than the in- institutional review board of the Univer- month (95% CI, 4.6%-19.9% per month) crease of infection on its return be- sity of California, San Francisco, and the (FIGURE 2). Treatment every 6 months tween treatments. National Ethical Clearance Committee is more than enough to eventually elimi- To model the future prevalence, the of the Ethiopian Science and Technol- nate infection. level of infection was extrapolated from ogy Commission (registered with the Of- Using these empirical data and the in- the observed prevalence data. The base- fice for Human Research Protections), equality above, we estimated the mini- line prevalence and the rate of return of prior to commencing the study. mum treatment frequency necessary for infection defined the parameters for a lo- elimination to be once every 11.6 gistic growth model. Mass treatments are RESULTS months (95% CI, 7.2-30.9 months), incorporated into the model by periodi- For the mass antibiotic distribution, 92% given 80% treatment coverage of the cally lowering the prevalence assuming of the total 10169 individuals aged 1 year population (FIGURE 3). This coverage 80% coverage and that the antibiotic will and older were covered by treatment, level of 80% was chosen for the projec- eliminate infection in 95% of individu- and 93% of the total 1478 children aged tions because it has been achieved by als treated. By varying the frequency of 1 to 5 years were covered, relative to the other trachoma programs17 and is the tar- these mass treatments, the resulting pro- census (N=24 villages). The 3 most get recommended by the WHO. The es- jections predict the feasibility of elimi- common reasons for not receiving treat- timation of the necessary treatment fre- nating infection. ment were temporary absence from the quency is locally sensitive both to the Results from 2 months and 6 months village at the time of treatment, migra- initial rate of return after treatment were compared using a t test paired by tion, and death. Refusal of treatment was (changing by 0.12 months for every 1% village. Intervillage variance was esti- rare. Village PCR participation rates were relative change in rate) and to the cov- mated, and confidence intervals (CIs) comparable at each time point, as de- erage level (changing by 0.32 months for were used to express uncertainty due picted in the TABLE. We found that every 1% absolute change in coverage to sampling error. All statistical calcu- 99.1% of negative field controls were level). The dependence of the neces- lations were performed in STATA 7.0 PCR negative (449/453). sary treatment frequency on the cover- (Stata Corp, College Station, Tex) us- Prior to treatment, the mean village age level is displayed in Figure 3. Also, ing the village as the unit of observa- prevalence of infection based on PCR the effect that the uncertainty in the es- tion. A local sensitivity analysis was per- positivity was 56.3% (N=24 villages; timation of the rate of return has on the formed by standard techniques16: 95% CI, 47.5%-65.1%). After treat- necessary treatment frequency is de- differentiating the necessary treatment, the mean prevalence dropped to picted in Figure 3 by the 95% CIs. ment frequency function with respect 6.7% (95% CI, 4.2%-9.2%) at 2 months; to either coverage or initial rate of re- by 6 months, it had risen to 11.0% (95% COMMENT turn, around the observed coverage and CI, 7.3%-14.7%) (P=.005 for 2 vs 6 These results imply that elimination of rate of return. PϽ.05 was considered months). Village-level prevalences at ocular chlamydia in this area of Ethio- statistically significant. each time point are categorized into vari- pia is feasible. Biannual treatment with

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ticular nonantibiotic measure has a sig- Figure 2. Mathematical Projections of Trachoma Prevalence Derived From Empirical Pretreatment, 2-Month, and 6-Month Posttreatment Results nificant effect on chlamydial infection, although there are reasons to be opti- 70 mistic.25 If true local elimination of ocular strains of chlamydia is feasible with 60 antibiotics alone, then this would pro- vide a rationale for the trachoma pro- 50 gram even without adjunctive mea- Observed Prevalence (95% CI) sures. If other measures prove to be as

40 Projected Prevalence effective as hoped, then antibiotics could Single Treatment Annual Treatment be given less frequently and to a lower Biannual Treatment 30 percentage of the population. Treatment The prevalence of ocular chlamydia in a community before treatment may be a 20 key factor determining the rate that infec- Prevalence of Infection in Children, % of Infection in Children, Prevalence tion returns after treatment—the greater 10 the baseline prevalence, the more rapid the return.11,26 Trachoma in this area of 0 0 1 2 3 4 Ethiopia is as severe as anywhere else in Time, y the world, so if biannual treatments can eliminate infection in this region, suc- Projections are based on the assumptions that treatment is administered once, annually, or biannually; coverage is 80%; and antibiotic efficacy in an individual is 95%.11 Projections follow logistic growth determined by the cess should be possible elsewhere, per- equation: baseline prevalence/(1 + Ce−[rate of return][time]), where C is a constant that is fit by the empirical data. haps requiring even less frequent treatments. Longer term empirical studies will munity after mass treatment, which has be necessary to determine whether infec- Figure 3. Treatment Frequency Necessary not been available previously for sev- to Eliminate Infection Over a Range of tion can indeed be eliminated locally and Antibiotic Coverage Levels eral reasons. First, most trachoma pro- to determine appropriate dosing frequen- grams monitor disease by following cies for less endemic areas. Although 48 clinical activity, which does not corre- studies have found only minimal pneu- late well with infection after antibiotic mococcal resistance after mass treat- 18,19 27 36 treatment. Also, intervillage vari- ment, the potential for emerging chla- ance is sufficiently high that multiple vil- mydial resistance should be monitored, lages need to be monitored to make a particularly when multiple rounds of 24 reasonable estimate.20,21 Finally, in some treatment are used. areas that have been studied, trachoma If mass periodic treatments with in- 12 appears to be disappearing even in the complete coverage of the population can absence of an organized control pro- eliminate trachoma as these results sug- Necessary Treatment Period, mo Necessary Treatment

0 gram, in which case infection may never gest, then researchers can concentrate 60 70 80 90 100 return after treatment.22-24 on whether similar results can be ob- Antibiotic Coverage, % Currently, the WHO’s goal for tra- tained by targeting only a core group The World Health Organization currently recom- choma programs is neither eradication most likely to be infectious. Mathemati- mends annual treatment. Calculations assume an an- (global reduction of infection to zero) cal models imply that this too is pos- tibiotic efficacy of 95% in an individual and use inequality (i). The solid black line indicates the calculated nor true elimination (local reduction of sible, although treatment may need to treatment frequency necessary for elimination; the infection to zero), but the more conser- be given more than twice per year.11 For dashed lines indicate 95% confidence intervals. vative target of “elimination of tra- many bacterial diseases, treatment tar- choma as a public health concern”.4 This geted to the entire population may not 80% coverage should be more than suf- is defined as less than 5% clinical activ- be appropriate. However, if only a core ficient to eventually reduce the local in- ity in children. The rationale of the pro- group needs to be treated, then mass re- cidence of infection to zero (Figure 2). gram is that infection can be reduced peat antibiotic administration may prove This coverage level is realistic and within with several mass antibiotic treat- to be a valuable tool for a variety of bac- the range of previous trachoma pro- ments, and that other sustainable, nonan- terial scourges. grams.17 Greater coverage would allow tibiotic measures such as face-washing less frequent treatment (Figure 3). These and fly control can prevent infection Author Contributions: Dr Lietman had full access to all of the data in the study and takes responsibility for calculations require estimation of the from returning to a community. So far, the integrity of the data and the accuracy of the data rate of return of infection into a com- it has been difficult to prove that any par- analysis.

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Study concept and design: Melese, Chidambaram, Statistical analysis: Alemayehu, Lee, Yi, Whitcher, National Institute of Allergy and Infectious Diseases Alemayehu, Yi, Whitcher, Gaynor, Lietman. Lietman. (grants R21 AI055752 and R01 AI48789), and the Acquisition of data: Melese, Chidambaram, Alemayehu, Obtained funding: Alemayehu, Yi, Whitcher, Gaynor, South Asia Research Fund. Pfizer provided azithro- Yi, Cevallos, Zhou, Donellan, Saidel, Whitcher, Gaynor, Lietman. mycin used in the study free of charge. Lietman. Administrative, technical, or material support: Melese, Role of the Sponsor: The funding sources of this Analysis and interpretation of data: Melese, Chidambaram, Alemayehu, Yi, Cevallos, Zhou, study had no role in the study design or conduct; Chidambaram, Alemayehu, Lee, Yi, Whitcher, Gaynor, Donellan, Saidel, Whitcher, Gaynor, Lietman. data collection, management, analysis, or interpreta- Lietman. Study supervision: Melese, Alemayehu, Yi, Whitcher, tion; or in the manuscript preparation, review, or Drafting of the manuscript: Melese, Chidambaram, Lietman. approval. Alemayehu, Yi, Donellan, Whitcher, Gaynor, Lietman. Funding/Support: This project was carried out Acknowledgment: We thank the field teams at ORBIS- Critical revision of the manuscript for important intel- through the support of the Osher Foundation, Ethiopia and the Proctor Foundation, and Stephanie lectual content: Melese, Chidambaram, Alemayehu, Lee, Research to Prevent Blindness, Pfizer International Costanza at the Proctor Foundation for their invalu- Yi, Cevallos, Zhou, Donellan, Saidel, Whitcher, Gaynor. and the International Trachoma Initiative, the able help with the project.

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