The Cochrane Library and trachoma: an overview of … · The Cochrane Library and trachoma: an...

EVIDENCE-BASED CHILD HEALTH: A COCHRANE REVIEW JOURNALEvid.-Based Child Health 2: 943–964 (2007)Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ebch.172

Overview of Reviews

The Cochrane Library and trachoma: an overview ofreviewsElizabeth Sumamo,1* Paul Emerson,2 Krystal Harvey3 and Matthew Burton4

1Alberta Research Centre for Child Health Evidence, University of Alberta, Edmonton, Alberta, Canada2The Carter Center, Emory University, Atlanta, Georgia, USA3Cochrane Child Health Field, University of Alberta, Edmonton, Alberta, Canada4Department of Infectious & Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK

Abstract

Background: Trachoma is the leading infectious cause of blindness worldwide. Active trachoma is caused bythe bacterium Chlamydia trachomatis. Recurrent infection over many years may lead to scarring of theconjunctiva, entropion, trachomatous trichiasis and corneal opacity.

Objective: To summarize Cochrane reviews that assess the effect of SAFE strategy (surgery, antibiotics, facewashing and environmental change) for trachoma in developing countries.

Methods: The Cochrane Database of Systematic Reviews was searched for any intervention to prevent ortreat trachoma. Data was extracted in duplicate and analyzed.

Main Results: There were four systematic reviews addressing trachoma, all of which met the inclusioncriteria. There was some evidence that the prevalence of active trachoma was reduced by the use ofantibiotics. At three months, six of nine trials found a significant reduction in relative risk of active trachomain the intervention groups. At 12 months, only three of six studies found a significant reduction. Oralazithromycin performed better than topical tetracycline at clearing infection at three months, but not atresolving clinical signs. There is evidence that face washing in combination with topical tetracyclineantibiotics can reduce the prevalence of severe trachoma compared to face washing alone. Insecticide spray asa fly control measure significantly reduced trachoma and health education may be effective in reducing activetrachoma.

Full thickness incision of the tarsal plate was found to be the most successful type of surgery for trichiasis.Tarsal rotation surgery was also found to be more effective than non-surgical techniques for minor trichiasis.This surgery was equally effective when performed by appropriate trained ophthalmic nurses andophthalmologists and also when conducted in a health centre or village setting.

Authors’ Conclusions: There are no clinical trials of the full SAFE strategy for trachoma control onblindness prevention, or on reducing active trachoma, or ocular Chlamydia trachomatis infection. However,there is some evidence that separately supports each of the components of SAFE: surgery, antibiotics, facialcleanliness, and environmental improvements. Programmatically, continued delivery of the full SAFE strategyis warranted and can be expected to have a positive impact on the control of blinding trachoma.

Editors’ note: Overviews of reviews, compiling evidence from multiple Cochrane reviews into one accessibleand usable document, are a regular feature of this journal. Our aim for each overview is to focus on the treatmentquestion, ‘which treatment should I use for this condition?’ It is our hope that the overview of reviews will serveas a ‘friendly front end’ to The Cochrane Library, allowing the reader a quick overview (and an exhaustive list)of Cochrane reviews relevant to the clinical decision at hand.

*Correspondence to: Elizabeth Sumamo, 9416-Aberhart Centre One, University of Alberta, Edmonton, AB T6G 2J3, Canada. E-mail:

[email protected]

Copyright 2007 John Wiley & Sons, Ltd.

944 E. Sumamo et al.

Background

Description of the condition

Trachoma is the leading infectious cause of blind-ness worldwide. Recurrent infection by the bacteriumChlamydia trachomatis produces a chronic keratocon-junctivitis (inflammation affecting both the conjunc-tiva and cornea) referred to as Active Trachoma. Theinfection is spread from person to person by fingersand clothes used to wipe away eye discharge. It is alsotransmitted through fly-eye contact (1). The repeatedcycle of infection and inflammation causes the innersurface of the upper eyelid to scar. Progressive scarringresults in distortion and shortening of the inside of theeyelid. As the lid margin turns inward (entropion) itcauses the eyelashes to also turn inwards and touch thesurface of the eye, a condition known as trachomatoustrichiasis. This condition can damage the cornea bydirect trauma and secondary bacterial infection unlesscorrected surgically, by rotating the lid margin andlashes away from the eye. Without surgical correc-tion, blinding corneal opacification can develop (2).Although trachoma is easily controlled, blindness fromtrachoma is essentially irreversible.

The World Health Organization (WHO) lists thenational trachoma prevalence estimates for 52 endemiccountries (http://globalatlas.who.int/globalatlas): appr-oximately 460 million people are at risk for blind-ing trachoma; 63 million have active trachoma; and9.5 million have unoperated trichiasis. It has also beenestimated that trachoma is responsible for 3.6% ofglobal blindness (approximately 1.3 million people)making it the world’s leading cause of preventableblindness (3).

Description of the interventions

WHO has adopted an integrated control strategyto prevent blindness from trachoma and to controltrachoma transmission. The strategy has the name‘SAFE’ and consists of: Surgery to correct trachoma-tous trichiasis; Antibiotics to treat active infectionsand reduce the community reservoir of infection; andFacial cleanliness and Environmental change to sup-press transmission by modifying factors that favour it(4,5).

How the interventions might work

Surgery is usually the first component of the SAFEstrategy to be implemented, as it can stop cornealdamage from progressing, and hence prevent blindnessin those at immediate risk, before irreversible cornealopacification has occurred (6). Epilation (plucking theeyelashes) and eyelid taping (forcing eyelashes backto the correct position and holding them with stickingplaster) can be used in lieu of surgery, although thelong-term efficacy of these interventions in preventingblindness is not certain. The most common surgicalprocedures are bilamellar tarsal rotation (full thickness

incision through the eyelid), posterior lamellar tarsalrotation (incision only through the scarred tarsal plateand conjunctiva) and tarsal advance and rotation(incision in the tarsal plate and rotation of the terminalportion, in which the upper part of the tarsus isseparated from the anterior lamellar and advanced) (6).All of the surgical procedures reverse the in-turnedlashes characteristic of trachomatous trichiasis so thatthey are returned to their original, outward-pointingposition.

For treatment with antibiotics, the WHO currentlyrecommends either: (a) 1% tetracycline eye ointmenttwice a day for six weeks applied topically on the innersurface of the lower eyelid, or (b) a single oral doseof azithromycin (1000 mg for an adult and 20 mg/kgfor children) (7). Antibiotics effectively treat currentinfections and are used for both individual treatmentand in mass drug administration (without individualdiagnoses) in hyperendemic communities to reduce thecommunity reservoir of ocular Chlamydia trachoma-tis. Mass drug administration is recommended in acommunity where the prevalence of the characteristicsigns of follicular trachoma (Grade TF in the Sim-plified WHO Grading System, (8)) exceeds 10% inchildren aged 1–9 years (7).

Washing the face removes potentially infectiousocular and nasal discharge from those with currentinfections who are shedding Chlamydia trachomatis,preventing contamination of fomites and reducinghand-eye transmission. Washing away the bacteriamay also play a role in reducing self-reinfection.Children with clean faces have also been observed tohave a reduced frequency of fly-eye contact with thetrachoma vector, Musca sorbens (9). This is importantin the reduction of both acquisition and transmissionof infection as flies that contact the eyes of childrenwho are shedding Chlamydia trachomatis can carrythe bacteria to the eyes of those who are not infected.The increase of clean faces is where the F and E ofthe SAFE strategy come together. Facial cleanlinessis implemented as hygiene promotion in its broadersense including personal grooming, use of soap, notsharing towels, and frequent washing of clothes andbed sheets, and this is facilitated and enhanced bythe provision of water and sanitation – which arethe primary Environmental changes that form the Ecomponent of SAFE.

Other environmental interventions that aim to con-trol eye-seeking flies and address other trachoma riskfactors include: water provision; reducing environmen-tal contamination with human faeces; promotion oflatrine use; moving animals away from domestic resi-dences; village cleaning with the promotion of refusedumps; and fly control with insecticides (2,10,11,12).

Some studies looked at infection with C. trachoma-tis in addition to active trachoma as an outcome. Therelationship between infection (as compared to clin-ical signs) and trichiasis and blindness is yet to be

Copyright 2007 John Wiley & Sons, Ltd. Evid.-Based Child Health 2: 943–964 (2007)DOI: 10.1002/ebch.172

The Cochrane Library and trachoma: an overview of reviews 945

established, but it is likely that the control of infec-tion in addition to reduction in clinical signs will beof long-term benefit.

Why it is important that we do this review

The brunt of the burden of blinding trachoma isborne by the most impoverished populations in theworld, populations whose poverty comes hand-in-handwith the unhygienic overcrowded living conditions andpoor access to water and sanitation, which are asso-ciated with trachoma. The economic impact of thedisability caused by trichiasis and blindness on thosewho are already poor contributes to keeping them inthe cycle of poverty. Trachoma has disappeared fromEurope, North America and individual countries with-out specific or large-scale control programs. It hasalso been demonstrated that it is possible to con-trol trachoma using the SAFE strategy in even themost disadvantaged parts of the world such as South-ern Sudan (13). The global elimination of blindingtrachoma should be possible, and it is necessary toinvestigate the efficacy of the interventions that aimto do so.

Objectives

To summarize Cochrane reviews related to the WHO’sSAFE Strategy, evaluating the effectiveness of inter-ventions to control active trachoma and to surgicallycorrect established trachomatous trichiasis.

Methods

Search Strategy

The Cochrane Database of Systematic Reviews wassearched for all systematic reviews examining anyintervention for the treatment of trachoma. The term‘trachoma’ was entered and restricted to record title,abstract or keyword. Four reviews were found, oneof which was being updated, and all of which wereincluded in this overview of reviews.

Selection of reviews

Each of the reviews retrieved assessed one of the fourcomponents of the WHO’s SAFE strategy to preventtrachoma; surgery, antibiotics, facial cleanliness andenvironmental changes (2,6,12,14). The characteristicsof the reviews can be found in Table I. All includedrandomized trials. While the focus of some of thesereviews was active trachoma and infection in children,adults were included in this analysis since mostinterventions to control trachoma are aimed at thecommunity and all the surgery trials were conducted inadults. Subjects in the trials of surgery and trichiasisrecurrence were graded as having major (more thanfive lashes touching the eye) or minor trichiasis (one

to five lashes touching the eye), or as having defectivelid closure.

Data extraction and management

Two authors, Elizabeth Sumamo (primary) and KrystalHarvey, were responsible for the extraction of outcomedata from the four reviews. Tables were created tocapture the statistical measures of interest; relativerisk (RR), risk difference (RD) and control group risk.Three community level trials adjusted for clusteringwithin their published statistics; however the RR andRD presented in this review was calculated at theindividual level without adjusting for clustering in theincluded tables (1,15,16). Any difficulties encounteredduring data extraction were discussed between bothauthors and all statistical issues were resolved withthe assistance of a biostatistician.

Assessment of quality of evidence

All reviews stated that the quality was assessedaccording to the methods set out in Section 6 ofthe Cochrane Handbook for Systematic Reviews ofInterventions using the Cochrane Eyes and VisionGroup Review Development Guidelines.

Data synthesis

The data were extracted from the four systematicreviews and displayed in Tables II, III, IV and V. Onereview had an analysis portion from which RR, RDand control group risk could be directly taken (2). Inthe other three reviews, not all the statistical numberswere expressed in this way. In one study, only oddsratios (OR) were reported and there was insufficientinformation available to calculate RR, RD and controlgroup risk (17). Besides this one instance, uniformreporting across all of the reviews was possible.

Involvement of authors

The team of authors for this overview of reviewsincluded Elizabeth Sumamo and Krystal Harvey whoextracted the data and participated in writing. MatthewBurton and Paul Emerson reviewed the data, edited thedocument and were the main authors for all sections.

Results

Four systematic reviews of 27 studies that examinedinterventions for trachoma control were found withinthe Cochrane Database of Systematic Reviews. Fouradditional recent studies were included due to theirhigh relevance and because they will be includedin future updates of included systematic reviews(16,18,19,20). The details of the individual studiesare found in Tables II, III, IV and V. The interven-tions to control active disease included topical and



Tab

leI.

Cha

ract

eris

tics

ofin

clud

edre

view

s

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ted

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mpa

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ibio

tics

for

trac

hom

a(2

)M

abey

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aser

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tN

Pow

ellC

Feb

2005

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ltsan

dch

ildre

n•

Topi

cala

ndor

alan

tibio

tics

atan

ydo

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frequ

ency

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pica

ladm

inist

ratio

nof

antib

iotic

sat

any

dose

orfr

eque

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aceb

oor

notr

eatm

ent

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rala

dmin

istra

tion

ofan

yan

tibio

tican

dan

ydo

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freq

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y

Prim

ary

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ctiv

etr

acho

ma

Seco

ndar

y-

Posit

ive

test

for

Chla

myd

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chom

atis

infe

ctio

n-

Adv

erse

side

effe

cts

Face

was

hing

prom

otio

nfo

rpr

even

ting

activ

etr

acho

ma

(14)

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assa

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2004

1–

14ye

ars

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ashi

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and

mas

san

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(12)

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razo

le+

oral

sulp

hadi

met

hoxi

netw

ice

daily

for

5co

nsec

utiv

eda

ysev

ery

mon

thfo

r5

mon

ths/

bi-w

eekl

yfo

r5

mon

ths

Tre

atm

ent2

:top

ical

sulp

hafu

razo

letw

ice

daily

for

5co

nsec

utiv

eda

ysev

ery

mon

thfo

r5

mon

ths

Com

paris

on:n

otr

eatm

ent

3m

o.10

4

12m

o.10

4

85.7

%

83.3

%

−0.3

9(−

0.55

,−0

.23)

−0.2

7(−

0.44

,−0

.10)

0.55

(0.4

1,0.

73)

0.68

(0.5

2,0.

88)

Tre

atm

ents

wer

epo

oled

and

com

pare

dw

ithco

ntro

l

Woo

lridg

e19

67(4

5)Tr

eatm

ent:

topi

calt

etra

cycl

ine

twic

eda

ilyfo

r6

cons

ecut

ive

days

per

wee

kfo

r6

wee

ksC

ompa

rison

:no

trea

tmen

t

3m

o.32

2

12m

o.32

2

85.8

%

83.3

%

−0.1

7(−

0.26

,−0

.08)

−0.1

0(−

0.19

,−0

.01)

0.80

(0.7

1,0.

90)

0.89

(0.7

9.0.

99)

Onl

yac

tive

trac

hom

aca

ses

trea

ted

Ora

lvs

topi

cala

ntib

ioti

cBo

wm

an20

00(2

4)Tr

eatm

ent:

oral

azith

rom

ycin

(sin

gle

dose

,20

mg/

kg)

Com

paris

on:u

nsup

ervi

sed

6w

eek

cour

seof

topi

cal

tetr

acyc

line

twic

eda

ily

10w

k.29

1

6m

o.29

5

53.2

%

27.0

%

−0.1

7(−

0.28

,−0

.06)

−0.1

5(−

0.24

,−0

.06)

0.65

(0.4

8,0.

86)

0.46

(0.2

8,0.

76)

Onl

yac

tive

trac

hom

aca

ses

trea

ted.

RRan

dRD

are

base

don

per

prot

ocol

anal

ysis;

thos

eth

atm

issed

follo

wup

are

not

incl

uded

(con

tinue

dov

erle

af)



Tab

leII

.(Co

ntin

ued)

Aut

hor/

year

Inte

rven

tio

nan

dco

mpa

riso

nN

o.s

ubje

cts

Co

ntro

lgr

oup

risk

[bas

elin

eri

sk]

Ris

kdi

ffere

nce

(95%

CI)

Rel

ativ

eri

sk(9

5%C

I)C

om

men

ts

Dar

ouga

r19

80b

(25)

Trea

tmen

t:or

aldo

xycy

clin

eon

edo

sepe

rm

onth

for

12m

onth

sC

ompa

rison

:top

ical

oxyt

etra

cycl

ine

twic

eda

ilyfo

r7

cons

ecut

ive

days

ever

ym

onth

for

12m

onth

s

3m

o.82 12

mo.

82

76.3

%

50.0

%

−0.0

4(−

0.22

,0.1

5)

0.05

(−0.

17,0

.26)

0.95

(0.7

5,1.

23)

1.09

(0.7

2,1.

66)

Hou

seho

ldtr

eatm

ent

Daw

son

1997

(28)

Trea

tmen

t1:

oral

azith

rom

ycin

(1do

seof

20m

g/kg

)T

reat

men

t2:

oral

azith

rom

ycin

(1do

se/w

eek

for

3w

eeks

)T

reat

men

t3:

oral

azith

rom

ycin

1do

seev

ery

4w

eeks

for

6do

ses)

Com

paris

on:t

opic

alox

ytet

/pol

ymyx

in+

oral

plac

ebo

once

daily

for

5co

nsec

utiv

eda

ysev

ery

28da

ysfo

r6

times

2m

o.16

0

1yr

.15

9

66.7

%

57.1

%

1D

ose

0.05

(−0.

15,0

.25)

3D

oses

−0.0

9(−

0.30

,0.1

2)

6D

oses

−0.0

3(−

0.23

,0.1

8)

Pool

edtr

eatm

ent

arm −0.0

2(−

0.19

,0.1

4)

1D

ose

−0.0

8(−

0.30

,0.1

3)

3D

oses

−0.1

4(−

0.35

,0.0

8)

6D

oses

0.04

(−0.

17,0

.26)

Pool

edtr

eatm

ent

arm −0.0

6(−

0.23

,0.1

2)

1D

ose

1.08

(0.8

1,1.

44)

3D

oses

0.86

(0.6

1,1.

21)

6D

oses

0.96

(0.7

0,1.

32)

Pool

edtr

eatm

ent

arm

0.97

(0.7

5,1.

24)

1D

ose

0.85

(0.5

6,1.

29)

3D

oses

0.76

(0.4

9,1.

19)

6D

oses

1.08

(0.7

5,1.

54)

Pool

edtr

eatm

ent

arm

0.90

(0.6

5,1.

23)

Onl

yac

tive

trac

hom

aca

ses

trea

ted

Fost

er19

66(4

2)Tr

eatm

ent

1:or

alsu

lpha

met

hoxy

pyrid

azin

eon

ceda

ilyfo

r5

cons

ecut

ive

days

ever

yw

eek

for

3w

eeks

Trea

tmen

t2:

topi

calt

etra

cycl

ine

3tim

esda

ilyon

5co

nsec

utiv

eda

ysev

ery

wee

kfo

r6

wee

ksC

ompa

rison

:no

trea

tmen

t

3m

o.21

8

12m

o.21

8

74.5

%

61.3

%

0.02

(−0.

09,0

.14)

0.10

(−0.

02,0

.23)

1.03

(0.8

9,1.

20)

1.16

(0.9

6,1.

41)

Onl

yac

tive

trac

hom

aca

ses

trea

ted

Scha

chte

r19

99i(

21)

Trea

tmen

t:or

alaz

ithro

myc

inon

cea

wee

kfo

r3

wee

ks(a

dults

1g,c

hild

ren

20m

g/kg

)C

ompa

rison

:oxy

tetr

acyc

line

once

daily

for

6w

eeks

3m

o.18

25

12m

o.19

41

25.7

%

19.6

%

−0.1

2(−

0.16

,−0

.09)

−0.0

5(−

0.08

,−0

.02)

0.52

(0.4

3,0.

64)

0.74

(0.6

1,0.

90)

Com

mun

ity-

wid

etr

eatm

ent.

Cou

ntry

:Egy

pt



Scha

chte

r19

99ii

(21)

Tre

atm

ent:

oral

azith

rom

ycin

once

aw

eek

for

3w

eeks

(adu

lts1

g,ch

ildre

n20

mg/

kg)

Com

paris

on:o

xyte

trac

yclin

eon

ceda

ilyfo

r6

wee

ks

3m

o.16

0012

mo.

1197

6.1%

15.7

%

−0.0

1(−

0.04

,0.0

1)

−0.0

7(−

0.11

,−0

.03)

0.76

(0.5

0,1.

15)

0.55

(0.4

0,0.

75)

Com

mun

ity-w

ide

trea

tmen

t.C

ount

ry:T

heG

ambi

a

Scha

chte

r19

99iii

(21)

Tre

atm

ent:

oral

azith

rom

ycin

once

aw

eek

for

3w

eeks

(adu

lts1

g,ch

ildre

n20

mg/

kg)

Com

paris

on:o

xyte

trac

yclin

eon

ceda

ilyfo

r6

wee

ks

3m

o.25

7712

mo.

2276

19.2

%

20.6

%

0.03

(0.0

0,0.

06)

0.04

(0.0

1,0.

07)

1.16

(1.0

0,1.

36)

1.19

(1.0

2,1.

40)

Com

mun

ity-w

ide

trea

tmen

t.C

ount

ry:T

anza

nia

Shuk

la19

66(4

3)Tr

eatm

ent:

oral

sulp

hadi

met

hoxi

nebi

wee

kly

orw

eekl

ydo

sefo

r5

mon

ths

Com

paris

on:s

ulph

afur

azol

etw

ice

daily

for

5co

nsec

utiv

eda

ysev

ery

mon

thfo

r5

mon

ths

3m

o.12

5

12m

o.14

5

85.7

%

56.5

%

−0.2

2(−

0.37

,−0

.07)

−0.1

3(−

0.29

,0.0

3)

0.74

(0.6

1,0.

91)

0.77

(0.5

5,1.

07)

Tre

atm

ents

wer

epo

oled

and

com

pare

dw

ithco

ntro

l

Tabb

ara

1996

(46)

Trea

tmen

t:or

alaz

ithro

myc

in(2

0m

g/kg

)C

ompa

rison

:top

ical

tetr

acyc

line

twic

eda

ilyfo

r5

cons

ecut

ive

days

per

wee

kov

er6

wee

ks

3m

o.64 6

mo.

56

37.5

%

34.6

%

0.09

(−0.

15,0

.33)

0.02

(−0.

23,0

.27)

1.25

(0.7

0,2.

23)

1.06

(0.5

2,2.

15)

Onl

yac

tive

trac

hom

aca

ses

trea

ted

Fac

ew

ashi

ngan

dhe

alth

educ

atio

nF

ace

was

hing

stud

ies

Peac

h19

87(2

2)Tr

eatm

ent

1:Te

trac

yclin

eey

edr

ops

daily

for

one

wee

kev

ery

mon

thfo

r3

mon

ths

Tre

atm

ent

2:Ey

ew

ashi

ngda

ilyfo

r3

mon

ths

Tre

atm

ent

3:Te

trac

yclin

eey

edr

ops

plus

eye

was

hing

Com

paris

on:N

otr

eatm

ent

3m

o.11

4375

.8%

Eye

drop

s−0

.09

(−0.

16,−

0.01

)

Eye

was

hing

0.02

(−0.

06,0

.10)

Eye

drop

s+

eye

was

hing

−0.0

7(−

0.15

,0.0

1)

Eye

drop

s0.

88(0

.79,

0.98

)

Eye

was

hing

1.02

(0.9

3,1.

13)

Eye

drop

s+

eye

was

hing

0.91

(0.8

2,1.

01)

No

met

a-an

alys

isco

nduc

ted

astr

ials

diffe

red

inse

vera

lre

spec

ts.

All

part

icip

ants

lost

tofo

llow

upas

sum

edto

have

follic

les

atth

een

dof

the

stud

yan

din

tent

ion

totr

eat

prin

cipl

ew

asap

plie

din

the

anal

ysis

ofre

sults

.W

est1

995

(17)

Trea

tmen

t:Fa

cew

ashi

ngpr

omot

ion

com

bine

dw

ithm

ass

tetr

acyc

line

oint

men

tC

ompa

rison

:Mas

ste

trac

yclin

eoi

ntm

ento

nly.

12m

o.14

17Pa

ir1

60%

Pair

250

%Pa

ir3

65%

Tet

racy

clin

eoi

ntm

ent

was

adm

inist

ered

topi

cally

once

daily

for

30da

ys.R

elat

ive

risk

and

risk

diffe

renc

esap

prox

imat

edfro

mpe

rcen

tage

s.D

iffer

ence

sar

eno

tst

atist

ical

lysig

nific

ant.

How

ever

,aut

hors

dono

tre

port

the

RRan

dRD

valu

es.

OR:

0.81

(0.4

2,1.

59)

(con

tinue

dov

erle

af)



Tab

leII

.(Co

ntin

ued)

Aut

hor/

year

Inte

rven

tio

nan

dco

mpa

riso

nN

o.s

ubje

cts

Co

ntro

lgr

oup

risk

[bas

elin

eri

sk]

Ris

kdi

ffere

nce

(95%

CI)

Rel

ativ

eri

sk(9

5%C

I)C

om

men

ts

Hea

lth

Edu

cati

on

Resn

ikof

f199

5(2

3)Tr

eatm

ent:

Hea

lthed

ucat

ion

one

wee

kpe

rm

onth

for

6m

onth

s.C

ompa

rison

:No

heal

thed

ucat

ion

6m

o.18

107.

1%−0

.03

(−0.

06,0

.00)

0.59

(0.3

4,1.

04)

Com

paris

ons

wer

eon

lydo

nebe

twee

non

evi

llage

and

the

cont

rolv

illage

.Ed

war

ds20

06(1

8)Tr

eatm

ent:

Com

mun

ities

targ

eted

byN

GO

san

dSA

FEst

rate

gy(s

urge

ry,a

ntib

iotic

s,fa

cew

ashi

ng,a

nden

viro

nmen

tal

impr

ovem

ents

)w

hich

rece

ived

radi

obr

oadc

asts

and

may

have

rece

ived

vide

osc

reen

ings

.C

ompa

rison

:Com

mun

ities

rece

ived

radi

obr

oadc

asts

only

12m

o.18

4266

.7%

−0.0

4(−

0.09

,0.0

1)0.

94(0

.87,

1.01

)

Env

iro

nmen

tals

tudi

esF

lyco

ntro

lint

erve

ntio

nsEm

erso

n19

99(1

5)Tr

eatm

ent:

spra

yw

ith0.

175%

volu

me

tovo

lum

ede

ltam

ethr

inup

to20

mou

tsid

eea

chvi

llage

.T

wic

ew

eekl

yin

the

wet

seas

onan

don

cew

eekl

yin

the

dry

seas

onfo

r3

mon

ths.

Com

paris

on-

No

inse

ctic

ide

spra

y.

3m

o.11

3415

.7%

−0.1

0(−

0.10

,−0

.09)

∗0.

39(0

.27,

0.56

)∗Bo

thEm

erso

n19

99an

dEm

erso

n20

04as

sess

inse

ctic

ide

spra

ybu

tno

met

a-an

alys

isco

nduc

ted

beca

use

ofsig

nific

ant

clin

ical

hete

roge

neity

.Em

erso

n20

04(1

)Tr

eatm

ent:

Spra

yw

ithw

ater

solu

ble

perm

ethr

info

r6

mon

ths.

Com

paris

on:N

oin

terv

entio

n

6m

o.48

506.

2%−0

.04

(−0.

04,

−0.0

3)∗

0.44

(0.3

3,0.

59)∗

Wes

t200

6(1

6)In

terv

entio

n:A

llm

embe

rsof

inte

rven

tion

balo

ziw

ere

give

na

singl

edo

seof

azith

rom

ycin

and

then

hous

ehol

dsan

dsu

rrou

ndin

gar

eas

wer

esp

raye

dw

ithin

sect

icid

e(1

0%pe

rmet

hrin

inw

ater

)th

roug

hout

the

year

.C

ompa

rison

:All

mem

bers

ofco

ntro

lbal

oziw

ere

give

na

singl

edo

seof

azith

rom

ycin

.

6m

o.22

9

12m

o.20

6

33%

44%

−0.1

3(−

0.25

,−0

.02)

∗

−0.0

1(−

0.15

,0.

13)∗

0.60

(0.3

7,0.

96)∗

0.97

(0.7

0,1.

34)∗

Obs

erva

tions

wer

eon

child

ren

aged

<8

year

s.O

bser

vatio

nsw

ere

onch

ildre

nag

ed<

8ye

ars.

Lat

rine

pro

visi

on

Emer

son

2004

(1)

Trea

tmen

t:La

trin

epr

ovisi

onC

ompa

rison

:No

inte

rven

tion

6m

o.28

366.

2%−1

.21

(1.2

2,−1

.20)

∗0.

72(0

.53,

0.96

)∗A

naly

sisw

asby

clus

ter,

and

not

indi

vidu

aln

=7

inea

chgr

oup.

∗ The

RRan

dRD

isca

lcul

ated

inth

isre

view

atth

ein

divi

dual

leve

lwith

out

adju

stin

gfo

rcl

uste

ring.



Table III. Severe trachoma

Author/year

Interventionand comparison

No.subjects

Controlgroup risk Risk difference

Relative risk(95% CI) Comments

Bowman 2000(24)

Treatment: oral azithromycin(single dose 20 mg/kg)Comparison: Unsupervised6 week course of tetracyclinetwice daily

6 mo.23 75% −0.55 (−0.91,

−0.19)0.27 (0.09,0.79)

Only those with severetrachoma at baseline wereincluded

West 1995 (17) Treatment: Face washingpromotion combined withmass tetracycline ointmentComparison: Masstetracycline ointment only.Tetracycline ointment wasadministered topically oncedaily for 30 days.

12 mo.1417(totalnum-ber ofpartici-pantsin trial)

Informationnotavailable

This paper only presentsodds ratios for theintervention villages

Severe trachoma: 0.62 (0.40,0.97)

Any trachoma: 0.81 (0.42,1.59)

Schachter 1999i(21)

Treatment: oral azithromycinonce a week for 3 weeks(adults 1 g, children20 mg/kg)Comparison: oxytetracyclineonce daily for 6 weeks

12 mo.1938 4.6% 0.01 (0.00, 0.03) 1.37 (0.91,

2.07)Community-wide treatment.Country: Egypt

Schachter 1999ii(21)


12 mo.1197 7.1% 0.00 (−0.02, 0.01) 0.83 (0.40,

1.70)Community-wide treatment.Country: The Gambia

Schachter 1999iii(21)


12 mo.2213 8.4% 0.03 (0.01, 0.04) 1.74 (1.17,

2.58)Community-wide treatment.Country: Tanzania

oral antibiotics at any dose or frequency, face wash-ing promotion with or without antibiotic treatment, flycontrol, and health education. Interventions for trichi-asis included bilamellar tarsal rotation, tarsal advanceand rotation, eversion splinting, tarsal advance, tarsal

grooving, electrolysis, cryotherapy, epilation, posteriorlamellar tarsal rotation, tetracycline and azithromycinat surgery, providing surgery in participants’ own vil-lage, and surgery by non-ophthalmologist integratedeye care workers.

Table IV. Chlamydia trachomatis infection

Author/year

Intervention andcomparison No. subjects

Control grouprisk Risk difference


Antibiotic versus controlDarougar 1980b(25)

Treatment 1: topicaloxytetracycline twice daily for7 consecutive days everymonth for 12 monthsTreatment 2: oraldoxycycline one dose permonth for 12 monthsComparison: vitamin pills 1dose per month for12 months

3 mo.129

12 mo.129

14.9%

19.1%

−0.05 (−0.17,0.07)−0.14 (−0.26,−0.02)

0.66 (0.25, 1.69)

0.25 (0.08, 0.78)

Intervention armsare pooled

Dawson 1969i(26)

Treatment: oraltrisulfapyrimidines 3 dailyduring 3 consecutive weeksComparison: lactose-placebo3 daily for 3 consecutiveweeks

3 mo.36 77.8% −0.17 (−0.46,

0.13)0.79 (0.50, 1.22)

(continued overleaf )



Table IV. (Continued)

Author/year

Intervention andcomparison No. subjects

Control grouprisk Risk difference


Dawson 1969ii(26)

Treatment: oraltrisulfapyrimidines 3 dailyduring 3 consecutive weeksComparison: lactose-placebo3 daily for 3 consecutiveweeks

3 mo.29 71.4% −0.25 (−0.59,

0.10)0.65 (0.35, 1.23)

Hoshiwara 1973(27)

Treatment: oral doxycyclineonce daily for 5 consecutivedays every week up to 28doses in 40 daysComparison: placebo oncedaily for 5 consecutive daysevery week up to 28 doses in40 days

3 mo.103 53.7% −0.05 (−0.24,

0.15)0.81 (0.63, 1.04)

Oral versus topical antibioticDawson 1997(28)

Treatment 1: oralazithromycin (1 dose of20 mg/kg)Treatment 2: oralazithromycin (1 dose/weekfor 3 weeks)Treatment 3: oralazithromycin 1 dose every4 weeks for 6 doses)Comparison: topicaloxytet/polymyxin + oralplacebo once daily for 5consecutive days every28 days for 6 times

3 mo.160

12 mo.138

7.3%

15.2%

−0.03 (−0.12,0.06)

−0.08 (−0.22,0.05)

0.57 (0.14, 2.30)

0.44 (0.15, 1.29)

Schachter 1999i(21)

Treatment: oral azithromycinonce a week for 3 weeks(adults 1g, children 20 mg/kg)Comparison: oxytetracyclineonce daily for 6 weeks

3 mo.1782

12 mo.1914

4.5%

6.2%

−0.04 (−0.05,−0.02)

−0.03 (−0.05,−0.01)

0.22 (0.11, 0.44)

0.48 (0.31, 0.74)

Community-widetreatment

Schachter 1999ii(21)


3 mo.1453

12 mo.1126

13.6%

13.5%

−0.07 (−0.10,−0.04)

−0.05 (−0.09,−0.01)

0.51 (0.37, 0.70)

0.62 (0.44, 0.87)


Schachter 1999iii(21)


3 mo.2538

12 mo.2236

6.2%

8.0%

−0.02 (−0.04,0.00)

0.00 (−0.02, 0.02)

0.68 (0.49, 0.95)

1.01 (0.76, 1.35)


Darougar 1980b(25)

Treatment 1: topicaloxytetracycline twice daily for7 consecutive days everymonth for 12 monthsTreatment 2: doxycyclineone dose per month for12 monthsComparison: vitamin pills 1dose per month for12 months

3 mo.82

12 mo.82

2.6%

2.6%

0.13 (0.01, 0.25)

−0.03 (−0.05,0.00)

6.05 (0.78, 46.95)

2.59 (0.28, 23.88)

Active Trachoma

Antibiotics and active trachoma

One review examined the antibiotic arm of theSAFE strategy by measuring the effects of antibi-otic treatment on both active trachoma and Chlamy-dia trachomatis infection of the conjunctiva (defined

as a positive nucleic acid amplification test resultfrom an ocular swab) (2). There were 15 includedtrials that randomized 8,678 participants and lookedfor the presence of active trachoma at either threeor 12 months after starting treatment. The reviewdivided the analysis of studies into those who receivedany antibiotics (topical or oral) versus placebo/no



treatment and those who received oral versus topi-cal antibiotics. Trial participants were usually residentin areas where trachoma is endemic, but were froma number of different countries and resided in vari-ous locations, including villages and boarding schools.One set of studies randomized entire communitiesrather than individuals to the intervention (21). TheWHO currently recommends either topical tetracyclineor oral azithromycin for individual and mass treatmentof trachoma, although the studies have used variousantibiotic treatment regimens.

(A) Antibiotics versus placebo/no treatment Summary statisticscould not be performed in studies where oral andtopical antibiotics were compared with placebo or withno treatment due to the degree of heterogeneity.

(I) Active trachoma at three monthsWhen measuring the effect of treatment with antibi-

otics on active trachoma at three months, the pointestimates were consistent with the antibiotics havingan effect with a risk reduction. The results were asfollows:

(a) any antibiotic(i) RR < 1 in six trials (P < 0.05)

(ii) RR < 1 in two trials (non significant(n.s.))

(iii) RR > 1 in one trial (n.s.)(b) oral antibiotics

(i) RR < 1 in three trials (P < 0.05)(ii) RR < 1 in two trials (n.s.)

(iii) RR > 1 in one trial (n.s.)(c) topical antibiotics

(i) RR < 1 in four trials (P < 0.05)(ii) RR < 1 in one trial (n.s.)

(iii) RR > 1 in one trial (n.s.)(II) Active trachoma at 12 months

The relative risks of study participants exhibitingactive trachoma at 12 months after treatment withantibiotic were consistent with there being no effect ofantibiotics at 12 months. The results are as follows:

(a) any antibiotic(i) RR < 1 in three trials (P < 0.05)

(ii) RR > 1 in three trials (n.s.)(b) oral antibiotics

(iii) RR < 1 in one trial (P < 0.05)(iv) RR < 1 in one trial (n.s.)(v) RR > 1 in one trial (n.s.)

(c) topical antibiotics(vi) RR < 1 in two trials (P < 0.05)

(vii) RR < 1 in two trials (n.s.)

(B) Oral antibiotics versus topical antibiotics When azithromy-cin or other oral antibiotics were compared withtopical tetracycline or other topical antibiotics, thedata suggest that oral antibiotics are neither morenor less effective than topical antibiotic treatment inreducing the prevalence of active trachoma after threeor 12 months.

When oral azithromycin versus topical tetracyclinewere compared, the point estimates of relative risk ofactive trachoma at three months were as follows:

(i) RR < 1 in two trials (P < 0.05)(ii) RR < 1 in two trials (n.s.)

(iii) RR > 1 in two trials (n.s.)

When other oral and topical antibiotics were com-pared, the relative risks of active trachoma at threemonths were as follows:

(i) RR < 1 in one trial (P < 0.05)(ii) RR < 1 in one trial (n.s.)

(iii) RR > 1 in one trial (n.s.)

When oral azithromycin versus topical tetracyclinewere compared, the point estimates of relative risk ofactive trachoma at 12 months were as follows:

(i) RR < 1 in two trials (P < 0.05)(ii) RR < 1 in one trial (n.s.)

(iii) RR > 1 in one trial (n.s.)

When other oral and topical antibiotics were com-pared, the relative risks of active trachoma at 12 mon-ths were as follows:

(i) RR < 1 in one trial (n.s.)(ii) RR > 1 in two trials (n.s.)

All of the trials were of poor to moderate qualityand intention to treat analysis was not performed inmost of them.

Face washing and active trachoma

There were only two trials included in the face wash-ing review. They employed different interventions andmeasured different outcome measures and therefore,meta-analysis was deemed inappropriate.

Face washing promotion combined with mass tetracycline ointmentversus mass tetracycline ointment only In the one studythat included this comparison, three pairs of villageswere recruited and one of each pair randomly assignedto tetracycline eye ointment only, with the otherassigned to combined intervention of tetracycline eyeointment plus a community-based behaviour changeprogram to promote face washing (17). All pre-schoolchildren in all villages were screened for clinicalsigns of trachoma at baseline and after 12 months. Inone pair of villages at 12 months, the prevalence ofactive trachoma (WHO grade TF) was lower in thevillage that received the combination of face washingand antibiotics (55%) than the village that receivedantibiotics alone (60%). In a second pair, the sametrend occurred and lower levels of active trachomawere found in the combination village (40%) than theantibiotic alone village (50%). In the third village, inwhich there had been poor uptake of the behaviourchange program, statistically similar levels of activetrachoma were seen in the combination village (70%)



Tab

leV

.Rec

urre

nce

oftr

acho

ma

tric

hias

is

Aut

hor/

year

Inte

rven

tio

nan

dco

mpa

riso

nN

o.

subj

ects

Co

ntro

lgr

oup

risk

[tri

chia

sis

atfo

llow

-up]

Ris

kdi

ffere

nce

Rel

ativ

eri

sk(9

5%C

I)C

om

men

ts

Surg

ery

tech

niqu

eA

dam

u20

02(2

9)1)

Bila

mel

lar

Tars

alRo

tatio

n(B

TR)

2)Ta

rsot

omy

(Tra

nsve

rse

Tars

otom

yan

dlid

mar

gin

Rota

tion

=TT

R)

3m

o.15

3pa

tient

s(2

56ey

es)

Min

ortr

ichi

asis

4.9%

Maj

ortr

ichi

asis

16.0

%

Min

ortr

ichi

asis

(TTR

asco

ntro

l)0.

06(−

0.07

,0.1

8)

Maj

ortr

ichi

asis

(TTR

asco

ntro

l)−0

.06

(−0.

16,0

.05)

Min

ortr

ichi

asis

(TTR

asco

ntro

l)2.

12(0

.38,

11.9

)

Maj

ortr

ichi

asis

(TTR

asco

ntro

l)0.

65(0

.29,

1.44

)Re

ache

r19

90(3

0)In

terv

entio

n:M

ean

follo

wup

per

grou

p7.

4to

8.8

mo.

Bila

mel

lar

tars

alro

tatio

n(B

TR)

Con

trol

s:1)

76ey

es1)

88.6

%1)

−0.3

1(−

0.52

,−0.

11)

1)0.

35(0

.17,

0.75

)

1)Ta

rsal

groo

ving

(TG

)2)

Tars

alad

vanc

ean

dro

tatio

n(T

AR)

3)Ev

ersio

nsp

lintin

g(E

S)4)

Tars

alad

vanc

e(T

A)

2)65

eyes

3)65

eyes

4)82

eyes

2)54

.2%

3)70

.8%

4)73

.2%

2)−0

.21

(−0.

45,0

.02)

3)−0

.37

(−0.

60,−

0.14

)

4)−0

.37

(−0.

56,−

0.17

)

2)0.

53(0

.27,

1.06

)

3)0.

32(0

.15,

0.68

)

4)0.

32(0

.15,

0.66

)Re

ache

r19

92(3

1)M

inor

Tric

hias

isTr

ial

9m

o.fo

llow

-up

1)Bi

lam

ella

rta

rsal

rota

tion

2)El

ectr

olys

is3)

Cry

othe

rapy

166

eyes

62.3

%−0

.51

(−0.

63,−

0.38

)0.

19(0

.09,

0.40

)M

inor

Tric

hias

is

Maj

orTr

ichi

asis

Tria

l9

or21

mo.

afte

rfo

llow

-up

1)Bi

lam

ella

rta

rsal

rota

tion

2)Ta

rsal

adva

nce

and

rota

tion

199

eyes

45.5

%−0

.27

(−0.

40,−

0.15

)0.

40(0

.25.

0.64

)M

ajor

Tric

hias

is

No

n-o

pera

tive

trea

tmen

tG

raz

1999

(32)

1)St

icki

ngpl

aste

r12

wee

ks2)

Stic

king

plas

ter

8w

eeks

and

epila

tion

4w

eeks

3)Ep

ilatio

non

ly

12w

eeks

3910

0%12

wee

kspl

aste

rvs

.Ep

ilatio

n−0

.71

(−0.

92,−

0.51

)

12w

eeks

plas

ter

vs.E

pila

tion

0.29

(0.1

5,0.

56)

100%

Cov

erag

e

Ant

ibio

tic

trea

tmen

tBu

rton

2005

(33)

1)U

nila

mel

lar

surg

ery

acco

mpa

nied

byun

supe

rvise

dte

trac

yclin

eey

eoi

ntm

ent

twic

ea

day

for

2w

eeks

asw

ella

ssin

gle

dose

azith

rom

ycin

toth

epa

tient

atsu

rger

yan

dsix

mon

ths.

Fam

ilym

embe

rsw

ere

also

trea

ted

with

azith

rom

ycin

atbo

thoc

casio

ns.

6m

o.41

0

12m

o.42

6

26.1

%

41.4

%

0.11

(0.0

2,0.

20)

0.00

(−0.

10,0

.09)

1.43

(1.0

7,1.

91)

0.99

(0.7

9,1.

25)

Med

ian

ages

ofth

egr

oups

are

57.3

and

57.2



2)U

nila

mel

lar

surg

ery

and

unsu

perv

ised

tetr

acyc

line

eye

oint

men

ttw

ice

ada

yfo

r2

wee

ksW

est

2006

(19)

1)Tr

ichi

asis

surg

ery

follo

wed

byW

hen

recu

rren

cew

asde

tect

edor

at12

mo.

1gof

oral

azith

rom

ycin

for

the

patie

ntor

singl

e-do

seaz

ithro

myc

in(2

0m

g/kg

upto

1g)

for

the

patie

ntan

dal

lhou

seho

ldm

embe

rs2)

Tric

hias

issu

rger

yfo

llow

edby

twic

epe

rda

yto

pica

ltet

racy

clin

efo

rsix

wee

ks

1406

6.8%

−0.0

3(−

0.06

,−0.

01)

0.53

(0.3

3,0.

85)

Mea

nag

esw

ere

50(h

ouse

hold

azith

rom

ycin

),48

.5(p

atie

nton

lyaz

ithro

myc

in),

and

48(t

etra

cycl

ine)

Zha

ng20

06(2

0)1)

Bila

mel

lar

tars

alro

tatio

nsu

rger

yan

da

singl

edo

seof

azith

rom

ycin

imm

edia

tely

afte

rsu

rger

y2)

Bila

mel

lar

tars

alro

tatio

nsu

rger

yan

dpl

aceb

oad

min

ister

edaf

ter

surg

ery

∗A

llpa

tient

sw

ithac

tive

trac

hom

aor

infla

mm

ator

ytr

acho

ma

rece

ived

tetr

acyc

line

oint

men

tat

base

line

and

follo

wup

.

6m

o.11

112

mo.

114

27.6

%

28.1

%

−0.0

1(−

0.18

,0.1

5)

0.02

(−0.

15,0

.18)

0.96

(0.5

2,1.

77)

1.06

(0.6

0,1.

89)

81.7

%of

popu

latio

nw

asag

ed>

40ye

ars.

Sur

gery

sett

ing

Bow

man

2000

(34)

1)Su

rger

yin

villa

ge2)

Surg

ery

inhe

alth

cent

re3

mo.

896.

3%0.

03(−

0.09

,0.1

4)1.

40(0

.29,

6.83

)M

edia

nag

ew

as53

and

56ye

ars

Cov

erag

ew

as66

%in

the

villa

gean

d44

%in

the

heal

thca

rece

ntre

s.P

erso

nnel

perf

orm

ing

surg

ery

Ale

may

ehu

2004

(35)

1)Bi

lam

ella

rta

rsal

rota

tion

carr

ied

out

byin

tegr

ated

eye

wor

ker

2)Bi

lam

ella

rta

rsal

rota

tion

3m

o.73

1

6m

o.

12.1

%−0

.03

(−0.

07,0

.02)

0.78

(0.5

1,1.

18)

3.2%

ofth

epo

pula

tion

wer

ech

ildre

nyo

unge

rth

an15

year

s.ca

rrie

dou

tby

At

sixm

onth

s,au

thor

sdi

dno

tre

port

spec

ific

recu

rren

cera

tes.

Aut

hors

repo

rted

nost

atist

ical

opht

halm

olog

istdi

ffere

nce

inre

curr

ence

betw

een

the

2ty

pes

ofsu

rgeo

ns.

(con

trol

)



and in the antibiotics alone village (65%). There wasan overall reduction in the odds of trachoma (WHOgrade TF) in the combined combination villages thanin the antibiotics alone villages, but this effect was notstatistically significant: OR: 0.81 (0.42, 1.59).

Tetracycline eye drops plus eye washing, eye drops alone, eyewashing alone versus no treatment Another study assessedthe efficacy of tetracycline drops alone, eye washingalone as well as their use in combination in reducingtrachoma infection (22). The relative risks of folliclesbeing seen at three months for each interventioncompared to controls were as follows:

(a) Eye drops + eye washing: RR = 0.91 (0.82, 1.01)(b) Eye washing alone: RR = 1.02 (0.93, 1.13)(c) Eye drops alone: 0.88 (0.79, 0.98)

The results suggested no statistically significantbenefit from tetracycline eye drops and eye washing,or eye washing alone compared to no intervention. Amodest benefit from eye drops alone compared to nointervention was reported.

Health education and active trachoma

Two studies measured active trachoma after a healtheducation intervention was delivered. One study founda significant decrease in relative risk associated withhealth education when compared to no education (23).The intervention included weekly information regard-ing personal and family hygiene and household sani-tation. Another study compared the rate of active tra-choma in communities targeted by non-governmentalorganizations (NGOs) and the SAFE strategy thatreceived radio broadcasts and video screenings againstcommunities who were not targeted by NGOs and whoonly received radio broadcasts (18). No significant dif-ferences in the rate of active trachoma at one year wereobserved between communities targeted by the SAFEstrategy and those who were not, but a small signifi-cant reduction was observed at the one year follow upcompared to the baseline survey (18).

Environmental factors

Three trials assessed the environmental arm of theSAFE Strategy (1,15,16). Emerson et al. 2004 lookedat the effect of insecticide spray and latrine provisionwhilst Emerson et al. 1999 and West et al. assessedinsecticide spray only. Meta-analysis was inappropri-ate due to significant heterogeneity between trials.

Insecticide spray versus no intervention on active trachomaAt three months one study, in which two pairs ofvillages were recruited and one of each pair randomlyassigned to insecticide spray whilst the other was acontrol, found there to be a prevalence of 6.2% in theintervention villages compared to 15.7% in the controlvillages (15). The relative risk of active trachoma at

three months was 0.39 (0.27, 0.56) suggesting thatinsecticide spray significantly reduced the magnitudeof active trachoma. In a second study, in which therewere seven pairs of insecticide spray and controlvillages, clinical signs of active trachoma (WHOgrade TF) were 55.8% lower in the interventionclusters compared to the control (1). The relative riskwas 0.44 (0.33, 0.59) at six months, indicating thatcommunity-wide insecticide spray also significantlyreduced the magnitude of active trachoma in thisstudy. A third study found a significant reduction (RR:0.60 (0.37, 0.96)) in active trachoma in children at sixmonths when insecticide spray was used on controlneighbourhoods rather than villages (16). When thisdifference was analysed by neighbourhood, however,a non-significant reduction was observed. There wereno significant differences in active trachoma betweenintervention and control groups at one year in thisstudy.

Latrine provision versus no intervention on active trachoma Theone study that looked at latrine provision found a29.5% reduction of active trachoma at six months(WHO grades TF and TI combined) in the clustersthat received latrines compared to the controls (1). Therelative risk was 0.72 (0.53, 0.96) when analysed atthe individual level, although the confidence intervalincluded 1.0 when analysed at the community level.

Severe trachoma (WHO grade TI)

Five trials captured data on the prevalence of severetrachoma (WHO grade TI). Detailed statistics fromthese studies are found in Table III. One trial used aface washing intervention while the others used antibi-otics (17,21,24). In the face washing trial the overallprevalence of severe trachoma was lower in childrenfrom the village from each of the three pairs that hadreceived a combination of face washing and antibi-otics (8%) than the villages that had received antibioticalone (14%) at 12 months. This difference was foundto be statistically significant: OR: 0.62 (0.40, 0.97).In the other studies the efficacy of oral azithromycinwas compared to that of tetracycline in three differentcountries, Egypt, The Gambia and Tanzania (21,24).One study found a significant effect of azithromycinover tetracycline at six months, whilst another studyfound no difference between azithromycin and tetra-cycline at 12 months (21,24).

Ocular infection with Chlamydia trachomatis

Antibiotics versus placebo or no treatment

When looking at C. trachomatis infection at threemonths, the point estimates in all four trials suggesteda reduced risk in the antibiotic group (2,25,26,27).However, none found a significant difference betweenthe pooled antibiotic and control groups (2). Onlyone trial reported outcomes at 12 months and found asignificantly reduced risk in the antibiotic group (25).



Oral antibiotics versus topical antibiotics

There were five trials assessing oral versus topi-cal antibiotics on C. trachomatis infection. At threemonths, a significant reduction in relative risk wasfound in three of the four trials that comparedazithromycin to a topical antibiotic whilst the fourthshowed a non-significant reduction (21,28). At 12months, there was a significant reduction in two tri-als, Dawson et al. found some reduction and Schachteret al. showed some increase (21,28). The fifth trialcompared oral doxycycline with topical oxytetracy-cline and found a non-significant increase at both threeand 12 months (25).

Process indicators

Active and severe trachoma and evidence of infectionwith Chlamydia trachomatis are the endpoints of mosttrials and have been discussed above. However, thereviews also assessed process indicators (clean facesand fly-eye contact) that are not in the tables and arereported in the narrative below.

Clean faces

In the only face-washing study that addressed thisoutcome, the percentage of children with clean facesincreased in both the combination face washing plusantibiotic villages and the antibiotic alone villages, incomparison to the controls (17). The effect was greaterin the face washing plus antibiotic combination vil-lages compared to the antibiotic alone villages: facewashing and antibiotic combination; 18% at baseline;to 33% at six months; and 35% at 12 months, com-pared to the antibiotic alone group: 19% at baseline;30% at six months; and 26% at 12 months. The dif-ference between the groups was statistically significant(P < 0.05).

Fly-eye contact

Two studies measured frequencies of fly-eye contact asa process indicator (1,15). The first study reported thatfly-eye contact by the trachoma vector, Musca sorbens,was decreased by 96% with the community-widespraying of deltamethrin in comparison to controls.The second study reported a reduction in fly-eyecontact by Musca sorbens of 88% with community-wide insecticide spraying with permethrin, and a30% reduction in villages that had received latrineprovision compared to controls. All three reductionswere statistically significant (P < 0.05).

Trichiasis surgery

The antibiotic, face washing and environmental com-ponents of the SAFE strategy are used to con-trol Chlamydia trachomatis transmission. The surgerycomponent aims to correct trachomatous trichiasis,which occurs as a result of repeated cycles of infec-tion and resolution of ocular Chlamydia infection; is

not, in itself, caused by current active trachoma. Theprimary outcome of surgery trials is usually the rateof recurrence of trichiasis after surgery. See Table Vfor results from the surgery trials.

Surgery techniques

In one study, there was no significant difference in therecurrence rate at three months between the bilamellartarsal rotation and transverse tarsotomy and lid marginrotation (similar to Trabut method) (29). In anotherstudy, bilamellar tarsal rotation was no more effectivethan tarsal advance and rotation RR: 0.53 (0.27,1.06), tarsal grooving RR: 0.35 (0.17, 0.75), eversionsplinting RR: 0.32 (0.15, 0.68) or tarsal advance RR:0.32 (0.15, 0.66) (30). In a third study, however,bilamellar tarsal rotation was more effective in treatingthose with minor trichiasis (one to five lashes touchingthe eye) than destroying the lashes by cryotherapy orelectrolysis RR: 0.19 (0.09, 0.40) (31). In those withmajor trichiasis (six or more lashes touching the eye),bilamellar tarsal rotation was more effective than tarsaladvance and rotation RR: 0.40 (0.25, 0.64). Therewas insufficient enrolment to assess these outcomesin those with defective lid-closure.

Non-operative treatment of trichiasis

At three months, one study found that using stickingtape alone was significantly more effective than epila-tion alone RR: 0.29 (0.15, 0.56) (32). The differencebetween epilation alone and sticking tape followedby epilation was not statistically significant (P = 0.5).The authors reported good clinical status as: no lashestouching the eyeball, complete lid closure, no con-junctival hyperaemia and no unplanned treatment nec-essary during follow up.

Post-operative antibiotic treatment

Three trials have examined the effect of post-operativeazithromycin on the recurrence of trichiasis (19,20,33).Two of these were published subsequent to the lastupdate of the surgery review (20,19). One trial foundno difference in trichiasis recurrence rates betweenpatients who had received post operative azithromycin(41.2%) and those who did not (41.4%) when assessedat 12 months (33). Another trial found no differencein the cumulative incident trichiasis recurrence ratesbetween the azithromycin treated group (29.8%) andthe placebo group (28.1%) at 12 months (20). Addi-tional sub-set analysis suggested that there may besome benefit from azithromycin for individuals whohad major trichiasis. The third and largest study con-cluded that a single dose of azithromycin was asso-ciated with a 33% reduction in trichiasis recurrence,compared with a 6-week regimen of topical tetracy-cline (19).



Surgery setting

One study that assessed people with major trichiasisfound that there were similar success rates (no recur-rence) between patients randomized to village-basedsurgery (91%) and health centre-based surgery (94%)at three months (34). In another study, the trichia-sis recurrence rates among patients who had surgeriesconducted by an ophthalmologist was 12.7%, com-pared to 9.9% among patients operated by an inte-grated eye care worker at three months (35). Thedifference was small and did not achieve statisticalsignificance, OR: 1.32 (0.83, 2.11). At six months,the difference between recurrence rates was again notstatistically significant.

Visual acuity as a surgical outcome

There were four trials in the surgery review thatassessed visual acuity following surgical and non-operative interventions. One trial reported that trichia-sis surgery improved vision but the degree of improve-ment was not quantified; however it was not statisti-cally significant (29). Another study found a statisti-cally significant improvement of about half a line ofSnellen Visual Acuity (P < 0.0001) following surgeryfor major trichiasis, but not those with minor trichia-sis (31). A third study reports an overall improvementin visual acuity of 0.14 LogMAR units 12 monthsafter surgery (P < 0.0001), however the data were notreported by randomization groups (33). Follow-up datawere not presented in the fourth study (35).

Uptake of surgical intervention

The uptake of intervention was only recorded in threestudies. One study reports that 38 participants refusedrandom allocation, with the refusal rate greater in thedefective lid closure group (31). Another study did notrecord attendance for treatment but mentions that therewere compliance issues (32). The third study statesthat surgical uptake was higher for those randomizedto village-based surgery (66%) than those who wererandomized to the health centre-based surgery (44%)(34).

Quality of life following surgery

Burton et al. examined quality of life after surgery,although this was not analyzed by randomizationgroup (33). Among all study participants, 77% reportedan improvement in vision and 94% felt more comfortin the operated eye.

Economic evaluation of surgery

Journey time and cost of travel was significantly lessfor clusters randomized to community-based surgerythan for those randomized to health centre-basedsurgery (34).

Adverse events related to surgery

Four studies reported on adverse events. No detailswere given but one study stated that lid-notchingand pyogenic granuloma were more common in thebilamellar than the posterior lamellar tarsal rotationoperations (29). The second study reported one caseof over-correction following bilamellar rotation andgranulomas in two lids (30). The third study reportedtwo cases of over-correction following bilamellartarsal rotations but none in the tarsal advance androtation group (31). The fourth study reported thatpatients found epilation to be less comfortable thansticking tape (P = 0.002) among those with unilateraltrichiasis (32).

Discussion

Trichiasis surgery

The authors of the Cochrane review on interventionsfor trachomatous trichiasis concluded that the mostsuccessful operation type involves full thickness inci-sion of the tarsal plate. Two main procedures arecurrently in use in most trachoma endemic settings:the bilamellar tarsal rotation and the unilamellar tarsalrotation. No convincing evidence was found that oneprocedure is better than the other, although the unil-amellar technique varied between studies. For minortrichiasis there is evidence that tarsal rotation surgeryis more effective than non-surgical techniques includ-ing cryotherapy and electrolysis. For mild trichiasis,however, epilation is commonly performed and hasnever been formally compared to surgery.

The review found good evidence that tarsal rotationsurgery can be performed equally well by appropri-ately trained ophthalmic nurses and ophthalmologists.This is of great programmatic importance as in mosttrachoma endemic countries the number of ophthal-mologists is very limited and the backlog of trichiasissurgery far exceeds what could be delivered by thesephysicians alone. The review also found evidence thatsurgery performed at community (village) level hadequivalent outcomes to that performed at a health cen-tre. However, the uptake was higher for village-basedsurgery, which is an important observation as in manyendemic regions the uptake of surgery is low.

The three studies investigating whether post-opera-tive azithromycin treatment improves surgical out-come have provided mixed results. Two were pub-lished after the last update of the review (19,20).Two studies found no convincing evidence thatazithromycin reduces trichiasis recurrence (20,33).The third and largest study did find a significant reduc-tion in trichiasis recurrence with azithromycin (16).This may have been because the study was conductedin a region where C. trachomatis infection is hyper-endemic. However, no difference in the prevalence ofchlamydial infection was demonstrated between thetreatment groups, leaving open the question of how



the antibiotic affected the outcome. The additionalantibiotic treatment of family members did not conferany extra benefit. Overall, it is difficult to reach anydefinite conclusions about the effect of azithromycinon trichiasis recurrence, particularly in an operational(rather than research) setting.

Antibiotics

The authors of the review of Antibiotics for Trachomafound only limited evidence that antibiotics reduce theprevalence of active trachoma. There were two maintypes of study. The first was a very heterogeneousgroup of trials of antibiotics versus placebo, in which,overall, the results are consistent with a modestbeneficial effect on active trachoma at three monthsbut not at one year of follow-up. However, most ofthese studies targeted treatment to individuals withsigns of active disease. Therefore, the full potential ofany antibiotic on controlling trachoma has probablynever been tested in a placebo-controlled trial, as theimpact of treatment in these studies is likely to havebeen greatly undermined by reinfection from untreatedmembers of the community.

The second group of studies compared oral with top-ical antibiotics. The authors of the review concludedthat there was no evidence of a difference in the resultsbetween topical and oral antibiotic treatment. We agreewith this conclusion with respect to clinically activedisease, but differ in our interpretation with respectto C. trachomatis infection. We consider that the evi-dence supports the view that oral azithromycin is moreeffective at clearing infection than topical treatment.However, the clinical significance of this finding iscurrently unclear because in these and other studiesthe inflammatory disease persists. One possible expla-nation for this disparity is that the resolution of theclinical signs of active trachoma has been found tolag behind the resolution of infection (36).

Face washing

The authors of the Cochrane review on the promo-tion of face washing for prevention of active trachomaconclude that from the available data there is some evi-dence that face washing, when combined with topicaltetracycline eye ointment, can be effective in reducingsevere trachoma. They additionally conclude that thecurrent evidence does not support a beneficial effectof face washing alone, or in combination with topi-cal tetracycline eye ointment, in reducing the preva-lence of active trachoma (14). Since the review waswritten there have been no additional clinical trials,although clean face, which has a variety of defini-tions, has been included in many observational studiesand cross-sectional surveys since the publication of theoriginal Tanzania ‘clean face’ study (17). The evidencefrom these studies has been summarized in a numberof traditional reviews (10,11,37). In the absence of astandardized definition of ‘clean face’ and without an

agreed-upon methodology of when and how it shouldit measured (the frequency of the components usuallyused to define a clean face such as food or dust on theface and the presence of ocular and nasal discharge arestrongly dependent on the time of day, season and ageof the child) it is difficult to interpret the findings ofthe risk factor studies. The difficulty in interpretation isexacerbated by the fact that two of the components ofan unclean face (ocular and nasal discharge) may be aresult of active trachoma. All of this notwithstanding,the results of the original trial on severe trachoma, andthe observational studies are considered to be sufficientto warrant the continued inclusion of behaviour changecommunication and promotion of personal groomingto promote clean face as one of the pillars of the SAFEstrategy (17).

Environmental change

The authors of the Cochrane review on the E com-ponent of SAFE conclude that there is evidence thatinsecticide spray as a fly control measure reduces tra-choma significantly, that latrine provision as a fly con-trol measure has not demonstrated significant trachomareduction, and that health education may be effectivein reducing trachoma. The authors note that there isa dearth of data to determine the effectiveness of allaspects of environmental sanitation in the control oftrachoma. Given the shortage of data available in thereview (shown again in Table II) and the heterogeneityof study design, a meta-analysis was not conducted. Inthe absence of any well-conducted intervention trials,there was no reference to the role of water provisionin trachoma control in the review, despite access towater being one of the major areas of implementationfor control programs.

Since the publication of the Cochrane review, twonew studies have been conducted that contributeadditional data (16,18). Edwards et al. examined theimpact of health education through radio broadcastsalone (control), radio plus routine non-governmentalorganization (NGO) program activities (standard), andradio plus NGO activities plus video (18). There wasa small and statistically significant reduction in theprevalence of clinical signs of trachoma in all thecommunities in the study, but no difference betweenthe three arms. The study lacked a true control armin which there had been no trachoma intervention,so the observed reduction in prevalence cannot beascribed with certainty to the health education. Westet al. examined the effect of insecticide spray forfly control after mass antibiotic treatment in an areaof central Tanzania hyperendemic for trachoma (16).The insecticide spray successfully and effectivelycontrolled eye-seeking flies, although there was nostatistically significant effect on either clinical signsof trachoma or prevalence of ocular swabs positivefor C. trachomatis at six or 12 months.

The Cochrane review references a number of tra-ditional reviews of the literature on the F and E



components of SAFE (10,11,38,39). Mabey et al.(1992), Mabey et al. (2003), and Kuper et al. alsoinclude useful discussion on the F and E compo-nents (37,40,41). These non-systematic reviews focusmainly on the numerous observational studies on tra-choma. Although it should be noted that trachoma hasdisappeared from Europe and North America, and nowfrom parts of the Middle East, as a result of improvedliving conditions and not as a result of programs basedon antibiotic distribution or surgery, the interventionsfor F and E currently being adopted in endemic areashave not been rigorously tested. Of note, there havebeen no clinical trials of improving access to water, useof latrines, hygiene promotion, trachoma health edu-cation, village cleaning, or moving domestic animalsaway from living quarters, all of which are currentlybeing used as trachoma control measures in one ormore countries.

Conclusions

Implications for practice

The control of blinding trachoma is based on theWHO endorsed integrated SAFE strategy. Whilst it isnot possible to state that there are sufficient rigorousclinical trial data to support or refute the use ofthe SAFE strategy for blindness prevention throughtrachoma control in its entirety, there is some goodevidence for each of the separate components.

There is a reasonably good evidence base to guidepractice in the surgical management of trachomatoustrichiasis. Surgery should involve a full thickness inci-sion and rotation of the terminal portion of the tarsus.Surgery can be safely and effectively performed byappropriately trained ophthalmic nurses. Results canbe equally good for surgery performed at the com-munity level, which can significantly improve uptakeof this intervention. Results of the post-operative useof azithromycin are mixed. Given the frequent con-junctival bacterial infection in people with trichiasis,it is appropriate to use some form of post-operativeantibiotic.

The evidence for antibiotics in trachoma control isconsistent with a modest risk reduction in clinicallyactive trachoma at three months post treatment, butnot at twelve months. The data suggest that oralantibiotics have a greater effect on C. trachomatisinfection than topical treatment at three months andpossibly one year. They appear to have an equivalenteffect on clinically active trachoma. The impact ofmass community–wide treatment may be much greaterthan treatment targeted at individuals with disease.However, this has not been formally assessed bya randomized placebo-controlled trial. It should benoted that the studies of mass azithromycin treatmentused three doses as opposed to the current WHOrecommendation of a single annual dose (21). Whetherthese regimens are equally effective is unknown. In

practice, the current recommendation that trachomabe treated with either topical tetracycline or oralazithromycin is unaffected by this review. There are,however, major gaps in the evidence on which tobase recommendations for the targeting, frequency andduration of antibiotic treatment.

For the F and E components, there is evidence thatface washing in conjunction with antibiotics has aneffect on severe trachoma, and that fly control withinsecticide spray reduces active trachoma. In terms ofprocess, face washing can increase the prevalence ofclean face and latrine promotion can reduce the fre-quency of fly-eye contact. Operationally, the inclusionof activities that support face washing and fly controlare warranted. These include hygiene promotion, waterprovision, fly spraying, latrine promotion and villagecleaning.

Implications for research

Each of the components of the SAFE strategy has beentested in isolation, but the impact of the full strategy onblindness prevention has never been tested. It wouldnow be ethically improper, however, to conduct a lon-gitudinal study of the impact of SAFE in comparisonto controls who were screened, but not included inimplementation activities. Fortunately, rigorous impactassessments of existing implementation programs, inwhich there are good quality baseline and follow-updata, coupled with monitoring data giving an insightto the intensity of the interventions delivered, shouldbe adequate. The A, F and E components of the SAFEstrategy share a common objective of contributing to areduction in transmission of the disease. Clinical trialshave usually tested just one of these components at atime, yet it could be anticipated that there is a syn-ergistic effect between them. Clinical trials that aredesigned to test the hypothesis that there is a syner-gistic effect of these three components of SAFE suchthat the effect of antibiotic is enhanced by face wash-ing and environmental improvements (and visa versa)should be conducted. For the individual components ofSAFE, a number of less complex operational researchstudies would enhance the delivery of programs.

Trichiasis surgery

The optimal management of minor trichiasis (one tofive lashes touching the eye) is uncertain. Currentlyboth early surgery and epilation are practiced. How-ever, it is unknown whether these are equally effec-tive. A randomized controlled trial of these alternativeswould be of programmatic value.

Recurrent trichiasis remains a significant problemwhich limits the effectiveness of surgery in preventingblindness. There is a need to assess simple approachesto improve the long-term outcomes. For example,absorbable sutures may be superior to the currentlyused silk. The outcome of surgery varies significantlybetween surgeons. Therefore, realistic strategies toaudit results and improve quality are necessary.



The uptake of surgery is often disappointingly lowparticularly among women who have a disproportion-ate burden of disease. The barriers to surgery probablyvary and need to be assessed in different regions.Strategies designed to overcome these, especially forwomen in rural areas, need to be tested.

Antibiotics

Mass antibiotic distribution programs are being setup in many trachoma endemic countries. For ethicalreasons, it is now unlikely that there will ever bea trial that investigates the effectiveness of massantibiotic against a placebo as there is a consensus thatthe current alternatives (oral azithromycin and topicaltetracycline) probably have some effect. However,there is a pressing need for evidence to help optimizetheir use. It remains uncertain who should be giventreatment, how often and for how long. Comparativetrials of different distribution strategies are needed.Given that the signs of clinically active trachoma canpersist long after the infection has been cleared byantibiotics, there is potentially a role for a simplepoint of care test for the infection to determinewhether a community needs an ongoing treatmentprogram.

Facial cleanliness

The combination of available trial and observationaldata is considered sufficient to warrant the continua-tion of hygiene promotion and face washing in tra-choma control programs. However a repeat of theoriginal face washing trial that included as processindicators azithromycin treatment and face washing,and that had both clinical and microbiological out-put, would be extremely useful. The current defi-nitions of clean face include ocular and nasal dis-charge, which are correlated with both the effectof face washing and the absence of disease. Thispotential impediment to interpretation will have to beaddressed in the study design and selected outcomeindicators.

Environmental improvements

Whilst there is evidence that insecticide spray for eye-seeking flies reduces active trachoma, other simple andsustainable strategies to control flies have not beentested. There is a need for large randomized controlledtrials of the effectiveness of latrines, village cleaning,and moving animals away from domestic residencesfor trachoma control. The effect of water provisionalone, or in combination with other routine trachomaprogram interventions, on the prevalence of trachomahas not been formally tested.

Declarations of Interest

None.

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