the first of in of

I{ORLD HEALTH ORGANI DE

ONCHOCERCCIASIS CONTROL PROGRA]IIME IN ^{WEST AFRICA}

PRGRA}{ME DE LUTTE CONTRE L,ONCHOCERCOSE EN AFRIQUE DE L,OUEST

A CO}IMUNITY TRIAL OF IVERMECTIN

IN THE ASUBENDE FOCUS ALONG THE RIVER PRU IN GHANA

Report

of the first

round

of ivernectin treatnent in

1987.

SUIiTMARY

The OCP has undertaken

eight

community

trials of

ivermectin during

1987-1988

with

as main

objectives to

determine

the risk of rare' but

severe adverse

reactions to

treatment and

to establish the potential of

ivermectin as

a tool in

transmission

control.

The

trial in the

Asubende area along the

river Pru in

Ghana was one

of the

most important

trials

^because

of the

large

population to

be

treated, the very high level of

endemicity and

the

favourable

conditions for ^a

transmission

trial. it

^was

also the first large scale trial to

be undertaken

following the pilot

study

in Bui.

Drug

delivery

^and

monitoring

of

adverse

reactions

^was done

in close collaboration with

the Onchocerciasis Chemotherapy Research Centre ^(OCRC) and

the Ministry of

Health

of

Gharra.

Between

7

and

l0

Oct,ober 1987,

a total of

14,488 persons were

treated

out

of a

census popuJ.ation

of 25,389.

Treatment coverage was ^61,27'

of the total population,

and ^74.2%

of the

population above

the

age

of ⁵ years.

The main

reasons

for not receiving

treatment were

the

age

limit of 5 years

(45,77") and

absence

(33,2%). _Of the

chi-l-dren

in the

5-11 years age group 4.6% were not

treated

bc,caust- the,y haC

a

bodl'rveight below 15

kgs.

The average dose of

ivermectin

rose from 152.7 ncg/kg

in the 5-9

^years age group

to

about ^16'1 mcg/kg

in

adults.

Treatme.nt had

a

major

effect

on

skin

and

ocular microfilarial

^loads

in

the

villages xith the highest microfilarial Ioads.,

Skin

nicrofilarial

loads had

failen by

^97%

after

two months

but

had

risen to

^10%

of their original

value at

the four

months

follow-up.

Ocular loads had

also

dropped

significantly,

in

particular in the

cornea where

the density of

dead

microfilariae

had dropped bt'95% and where

virtualll'no living microfilari&e

were seen anJ'more

after four

months.

The tre,.rled population rvas mon

itored

^f

or the possible

occurrence of adverse

reactions during the first

72 hours

following

Lreatment, and the observed

reactions

were recorded and graded according

to a

standardized

procedure.

A

total of

52 severe

reactions (3.6 per

1000

treated)

were

observed,

i.e.

:17 cases

of

Severe Symptomatic

Postural

Hypotension (SSPH)' ¹³ cases

of

severe

fever

and two cases

of

severe Dyspnoea. Though

the latter

t.tio

rt-presented dangerous

life threatening situations, there

^{was no evidence that}

tlrel

represerrt complications

of

ir-ermectin

treatment.

^OnIy

four of the

^SSPH

ciirses reclrr i

red

treatment ^w i

th

hydrocort ⁱ

sone.

^AI

I

cases

of

severe adverse reacti.ons were,managed

successfully

and

aIl

^recovered

within 2

dap's, and

rrsrralll't'ven rriLhin a period of a

few hours.

.\l

I

^mi

Id

and moder;rl.e

reactions

were

also

^recorded

in villages with

^a

residerrt

monjt.oring

team.

^15.5%

of the treated population

reported

with

^a

rt:ac't

iorr

Lo

treatment.

The most common

reactions

were

pain conditiolis

and

lever, rvhile

cutaneous

rt-actions

were

less frequent

than expected.

Surprisingll,common were

swelling

and gland

reactions.

Simple treatmetrt in

the

^f orm

of

lraracetamol, and ^some phenerqian

or chloroquine,

^Has pro'i'ided to

,l 5.9%

of tlre

reported

cases.

The incidence

of

ad'r,erse

reactions

itrcreased wi t.h

the

Iev,,'l

of

^cndr-.mic i t,y

of the

^{v i}

Ilage,

^{ever) though some severe reactions} r.r.re noted

irr

t.lri

rrl

I

ine

^r

il iaqes. \'irtuall1'

no react-ions were report-ed

during-.

the tlal'ol' treatnr<'nt.

I'he lrrghest incidence occurred

during the

1st fol1ow-up da1',

in particular for

^SSPH

for

which 85% were reported

during

the

first

day

of follow-up.

There was

a highly significant relationship

^between

the

incidence

of

adverse

reactions

and

the intensity of infection of

the person

treat.ed, but the risk of

adverse

reactions

was

not related to

the

actual

dose

of ivermectin

received

within the

observed dose range

of

130

-

²⁰⁰

mcg/kg bodyweight.

I t'

Delayed

reactions

^were

reported in

¹³

^patients during a

12 weeek follow-up

visit in the

&rea, and sone

of

these were

also severe.

The

relationship

between these

reactions

and

ivermectin treatnent is

unknown

but

these

findings necessitate follow-up visits after

^{14 days}

in

subsequent

trails.

Vector

control

was

interrupted fron

30 June 1987

in order to allow

a

vector

population

to build up. This vector

population

stabilized

around ¹ September 1987 and

daily vector collection

was

naintained fron that data tiIl

11 February 1988 when

vector control

was resumed. Conpared

to

^{previous years}

the biting rate

was

high at

about 200

per

day and

the

population was

relatively

^young

with a

^parous

rate of 47%.

The

infection levels in

the

vector

were

fairly stable during

September

but started falling rapidly

around

the time of ivermectin distribution in

October, and

stabilized at

about 27% of

the

pre-treatment

level. After taking the

entomological

pre-control data into

account and

correcting for differences in fIy age-structure

and dissection methods,

it is

conluded

that ivermectin distribution in the

Asubende area has

reduced transmission

during the first three

months

after

treatment

by

70-75%.

I.

INTRODUCTION

II.

^{THE STUDY AREA}

Page 1

Geographical

location.

Population

Entonological

situation Epideniological situation

III.

^STIISIARY QE ^{STUDY DESIGN}

IV.

^{MASS TREATMENT I{ITH} IVER}TECTIN.

rv.1.

IV. 2.

rv.3.

IV. 4.

II.1.

11,2,

II;3.

II.4.

VI .2

vr.3

VI .4

vr.5

2 2 5 5 5

7

9

Organization

of ivermectin

treatment and monitoring

of

^adverse

reactions

Census

population,

treatment coverage and ivermectin ^dosage.

Effect

on

skin microfilarial

Ioads

in the

holo-endenic

villages.

Effect

^on

ocular microfilarial loads in ^the

holo-endenic

viIlages.

20 20 20 24 24 26 26 28 9 9 14 18

31 31 34 37 37

V.

^{ADVERSE EVENTS} FOIIOWING IVEBMECTIN TREATMENT

Monitoring

of

^adverse reactions.

Quantification of

Adverse Beactions Severe Adverse Reactions

. SSPH

.Blood pressure _changes

following ivernectin

treatment

. Dyspnoea

Adverse

reactions in villages with resident nonitoring.

Incidence

of

adverse

reactions in relation to

ager

sex, intensity

of

infection,

bodyweight and

ivernectin

dosage.

V.5.1.

Holo-endenic

villages

V.5.2. AII villages with resident nonitoring

Day

of first reporting

and symptonatic

treatnent of

adverse reactions Delayed Reactions

VI.

^EFFECT OF MASS TREATMENT ON TRANSMISSION.

VI.1 Vector

Biting

and Parous Rates

during the

Study

Period (July

1987- February 1988 ₎

Changes

in

Vector

Infectivity during

1987 Page39

Changes

in

Vector

Infectivity

conpared

to

^{Previous Years}

Estinated Reductions

in

Transnission

Relationship between Entomological and Epidemiological ^Changes v. 1.

v,2, v.3.

v. 4.

v. 5.

v.3.1 v,3.2 v.3.3

v.6.

v,7 ,

38

38 42 44 46

page

I.

INTRODUCTION

Since

the start of operations in

^1975,

the

Onchocerciasis Control

Programme (OCP) has had

to rely

on

vector control

through

larviciding

as the

sole

method

available to

achieve

its objective, i.e. to ^put

an end to

onchocerciasis as

a PubIic

Hea1th and Socio-Economic problem and

to

ensure

that there will

be no recrudescence

of the

disease

thereafter. Apart

from a

few

isolated failures, ^vector control

has been extremely successful

in

the

original

^OCP area where

the

disease

is

^under

fuII control

and

the

parasite

reservoir in

^man

is rapidly

dying

out.

^{The present}

control

operations involve weekly

aerial

spraying

of Iarvicides

over

a vast territory in

eight

West-African

countries,

and

vector control is

an expensive and manpower

intensive

undertaking which cannot be sustained

indefinitely nor

taken

over

^by.

the

Hest

African countries concerned. It

has

for several

^years been

recognized

that the long

term success

of

onchocerciasis

control

would require

the

devclopment

of

chemotherapeutic agents which could be used

effectively,

simply and

safely in

^mass

treatnent of

onchocerciasis under

field

conditions.

The

recent

emergence

of ivermectin

&s an

effective

and apparently weII

tolerated microfilaricide

and

its registration in

France

in

October 1987

is

Lherefore

of ^great i.nterest to the

^OCP.

The OCP began

in

1986

to investigate

how ivermectin might be

utilized

as

a cost-effective operational tool in the control of

onchocerciasis and

it

was concluded

that

two major questions needed

to

be answered before

operational

plans could be

made.

The

first

concerned

the risk of rare

but severe adverse events

following ivermectin treatment, a

^question which had not been resolved

during the clinical trials.

The second question _concerned the

potential of

ivermectin mass treatment as

a

tool-

for controlling

transmission, whether as &n

adjunct to larviciding or

as

a replacenent.

The OCP enbarked on

an ambitious ^programme

of eight

community

trials of ivernectin during

1987 and

1988

in order to

answer those

questions.

One

of the nost

important

of

these

is the trial in the

Asubende focus where

the first

round

of

ivermectin was

given in

^October 1987.

Since

ivermectin is

an

effective microfilaricide, it is

expected

that

^mass

treatment

with

ivermectin

wiII result in

an immediate

reduction

in

transmission.

However,

it is not very evident

how much

reduction

can be

achieved

given that ^part of the

population

will not receive treatment,

whether because

they falI

under

the

exclusion

criteria or

because

of other

reasons such

as refusal

and temporary absence, and

that

^even

in

those

treated not all microfilariae wil]

be

eliminated.

Before any conclusion could be drawn on the

operational potential of ivermectin for

transmission

control, it

was necessary

to first

determine

in a

well-designed study

the

maximum

reduction in

transmission which can be achieved

by

ivermectin mass treatment under optimal

conditions

and

with

maximal coverage

of the population involved in

^the

transmission

cycJ.e.

Such

a

study received

the highest priority

and

the

chosen stud-v ar(ja was

the

Asubende focus along

the river

Pru

in

Ghana.

The Asubende focus

is in

^many respects

the ideal

area

for a

study

of

the

operational potential of ivermectin for the control of

O.voIvulus transmission

in the

West-African savanna and

definitely the

most

suitable focus in the

OCP.

The reasons

are that it

concerns

a well-defined, isolated

focus

of

hyperendemic ottchocerciasis

with a

IocaIlS' closed transmission

cycIe.

^The

vector is nearly exclusively the

savanna subspecies

of

S.damnosum

s.I.

and the area

is free of reinvasion by infective vectors

form el"sewhere. With the e:xception

of a

few months

in

^1985,

the

area has

not

come under

vector control till

1986 which

is too recent to

have

resulted in a

change

in

the

epidemiological

situation.

Even

during

1986

vector control

was interrupted

twice,

and another

interruption of control during

1987

for the

purpose

of

the

study,

would

epidemiologically

be

justified if

such an

action is

accompanied

by ivermectin

treatment

of the infected population.

Extensive entomological dnt.a

of a very high quality

have been

collected since

January 1978 and have

ps.ge 2

resulted in

an unique

data

base on transmission

in a

non-control-Ied area.

These

data

form

the ideal

entomological baseLine

information to

determine the

reduction in infectivity levels in the vector population,

achieved by mass

treatment

with ivermectin

as

the sole

method

of control.

Before

the start of the

conmunity

trials,

ivermectin had

only

^{been used} in

the

treatment

of

^selected cases

during the clinical trials,

and

the

number

involved has been

too small to allow

an &ssessment

of the risk of rare,

but

serious,

adverse

reactions following treatment.

However,

the utilization of

Lhe

drug for

^purposes

of transnission control implies regular

^mass treatment

of large

populations

over

^prolonged

periods in

remote

areas,

^{which have} often

Iittle or

no

health facilities,

and where

it wiII

^be

difficult to nonitor

the

population for the possible

occurrence

of serious

adverse

reactions.

Before sucb

large scale distribution could

be undertaken,

it

was necessary

to arrive

aL

a better

understanding

of the risks

involved

by treating a large

^number of patienLs

in studies with a sufficient level of ^post

treatment monitoring of adverse

reactions.

The Asubende

study

ranks

also high

among

the

community

trials

^because

of ^{the size} of the population to

be

treated (it

turned

out

to be

the largest study)

and because

the

monitoring was undertaken in

collaboration with the

Onchocerciasis Chemotherapeatic Reseach Centre ^(OCRC)

in

^TamaIe which ensured

clinical

monitoring

of

exceptional

high quality

during

the

Asubcnde

trial.

OBJECTI VES

The two

principal objectives for the

study

with

mass

ivermectin

treatment

in the

Asubende focus were:

-

^To determine,

during a period without vector control, the effect of

^mass

ivermectin treatnent in the

Asubende focus on

the

loca1

transnission

of

O.volvulus,

&s measured

by

entomological indices.

-

^{To monitor}

^{during the} first

⁷² hours

following

treatment

the total

treated

population for the possible

occurrence

of serious*

^adverse

reactions

and ^a selected

population for the

occurrence

of Iess

severe adverse reactions which

result in transient incapability to carry

on normal

activities;

^and

to

do

a follow-up in the Iarger

settlements

after 3, 6

and 12 months.

[*

^A

^serious

^adverse

^reaction is defined

as an adverse

reaction

^which

constituLes a definite

^hazard

to the patient or offspring that

^can

be considered

life-threateping. This

includes

death,

decreased

Iife-expectancy,

^permanent

disabilitt', congenital

^{anomaly' cancer} and

other

experiences which

require hospitaltzation.]

II.THE ^{STUDY AREA}

I I .

1.

Geographical

location.

The Asubende

focus is

Iocated along

the

most downstream

stretch of

the

river

Pru

in

Ghana,

just before the river flor''s into the Volta

Lake ^(see

figrrre 1 for

locaLion

of ^the

area and

figure 2 for a detailed

map

of

the Asubencle

focus).

^Though

not far

from Lhc

forest, the

Asubende

focus is still

sirvanna count.ry and has always been an

integral ^part of the

West-African savanrla

bc'It tiII it

was

cutt off

^when

the Volta lake

was

created.

As ^a

result, the

area has become

an isolated

savanna focus enclosed between the

\;o1ta LaI<e

in the

East and

in the North,

and

the

Wr:st-African

forest belt

ⁱⁿ

Lhe South and

in the West.

The

centre of the focus is a river stretch

of about 25

kilometers long,

upstream from

the vi)-lage of

Prang, which contains

the

breeding

sites for the vectors

which

are responsiblc for

O.volvulus 1-ransmission

in this

area.

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II 2,

Population

A problen

in

study design was

the lack of recent

census

infornation

and

accurate naps

of ^the

^Asubende

focus.

^A

^special

reconnaissance

nission

^was

therefore

organized

by the

OCP

in order to

nap

aII

^hunan settlements

in

the study area and

to obtain

reasonable

estinates of the population

^involved.

Mapping was done by

overflying the

^{area by}

helicopter

and

the identified

settlements

are

shown

in the

attached nap

of the

area ^(see

Fig.2). It

^was

found

that the population density is ^quite high for

^{an area}

^with

hyperendenic

onchocerciasis.

The

villages

located along

the niddle of the

breeding

site are very snall

as would be

expected.

However,

it is surprising to find

as a

first line settlenent a village (or rather a

town)

like

Prang

with

nore than 5000

inhabitants.

The

total population Iiving ^within a

distance

of

²⁰

kilometers

from

the river is

^{about 25000}

people. Accessibility in the

area

is

reasonable,

with

^good roads from Atebubu

to the

North and from Prang to

Abease.

The

villages are weII

organized and

nost of

^them have schools.

Furthermore,

there are three well staffed clinincs in

^{Prang, Abease and}

Atebubu respectively.

II.3.

Entomolorical

situation

Entonological data have been

collected since

^{January 1978}

at a

catching

point

near

the village of

Asubende. Catching has been done on

a very

regular

basis with

an average

of

73 catching days

per

year _and

a total of

^44'097

flies

caught

of

which

nearly

25,000 have been

dissected.

^The Annual

Biting

^Rate

(ABR) _w&s on average 25,640

but varied

considerably over

the years.

The

Iowest

pre-control levels

were recorded

during the

two years

of

drought

in

1982 and

in

1983, when

the

ABR

feII

below 7,000

but during nornal

^years the

ABR reached

easily values

of. 251000

to

35,000

bites ^per

nen

per year.

The

Annual Transnission

Potential

^(ATP)

varied in

accordance

with the

ABB'

but

had

generally a

value

of

nore than 21000

infective larvae per

^person

per

year which

indicates a fairly high level of transmission.

Morphological

characteristics of all but a

few

flies

were

consistent with the

assunption

that the vectors constitute a

pure sav&nna population _and

all larvae

^sanpled from

the

breeding

site

were

cytotaxononically classified

as S.damnosun

s.s

or

S. sirbanum.

II.4. Eoideniological situation

The Asubende focus was

not

included

in the original

^OCP area and

in

the

past only

one

epideniological

survey has been undertaken

in this focus.

This survey was done

in

1980

in the village of

Asubende

after

which

the

focus

is naned.

However,

in

preparation

of the ivermectin study, the

epidemiological

evaluation unit of the

OCP has undertaken

skin snip

surveys

in

10

villages

in

the

area

in order to provide a better

baseline

description of the

endenicity and geographical

distribution of

onchocerciasis

infection in this focus.

^Four

of

these surveys were done

using the routine

OCP nethodology

for

sinple

surveys and included

a fuII

census,

a visual acuity test

and

skin

snip

exanination

after

30 minutes

incubation in distilled water. In the

renaining

six villages a less rigorous, rapid

assesslnent nethodology was used

in

^order

to obtain additional information

on

the

geographical

distribution of

infection. This

nethod

involves skin snip

examination

after

^{24 hours}

incubation in saline only

and does

not include a

census and

visual acuity test.

#

page 6

The

nain findings

from

aII ten

surveys &re sunnarized

in table 1. It

can

be seen

that the

prevalence

and, in particular the

CMFL, becomes

significantly

reduced

with increasing distance fron the

breeding

site.

Neverthelees, the

intensity of infection is still inportant in the

second

line villages,

and,

though

the intensity of infection is quite low, the

prevalence

is

not

negligible in the third line villages

which were

visited. It

seens therefore

that the population over a

considerable area

is involved in the

transuission

cycle,

and on

the _basis of

these

results the estinate of the

population

to

be

treated in the trial (originarry

_estimated

at

^{g000 people}

onri)

had

to

^be

revised

considerably.

TAbIC

1:

SUMMARY OF MAIN EPIDEMIOLoGICAL _RESULTS FoR 10 SURVED vILLAGES

(A).

SURVEYS WITH OCP STANDARD METHODOLOGY

Vi I

lage

_Type

of Census

Examined

Name Village population

population

: ==== ===== ===================================

Standard i zed

Prevalence

CMFL

of

mfs (Z)

=========================

Asubende Faowomong

N i aope

Bupe Abease Nyameas

i

YakpaI i Bassare Bankama

1

lst Iine lst

I ine

lst line

542 183 t67

510 166

t29 ^85. 87. ⁶3

85. 6 66. I

72.8 57.8

5.7r

3 .21

Akrukube

_{2nd I}

ine

177

(B).

SURVEYS WITH RAPID ASSESSMENT METHODOLOGY

t7l

L92 454 352 195 265 72

67 .7 2t. 4

lst

2nd 3rd 3rd 3rd 3rd

l rne I ine

lrne Iine

I ine

I ine

404 105 3 799 381 567 301

57.

48.

41.

29. gr

11 .1r

78 68 56

8 7 2 0 4 8

.6r 11.7r

The GMFL's obtained

with the rapid

&ssessnent methodology

are

based on skin

snip

readings

after

24

hours.

Tire

results

_{have been}

nultiplied _{with a}

_conversion

f;":?1,,::"r"uu

^then conparable

*itr, tn" results of the

standard readings

after

-fu., ^"

III.

^SUMMARY OF ^{STUDY DESIGN}

Since 1986,

the

Asubende

focus is

under

effective vector control

and the

vector density is usually negligible.

To enable

the study it

^was therefore rrecessary

to interrupt local larviciding

and

to allow the vector

to

temporarily

repopulate

the

breeding

site. It

^was considered

that this

^was

fully justified

on

ethical

^{grounds, given}

the short period that this

focus has been under

control

and

the

important

benefit

ivermectin treatment was

IikeIy to bring to the heavily infected population in this

hyperendemic focus.

However,

vector control in the

Asubende focus does

not only

serve

to

^protect

the local population

from

infection, ^{but also} to

^prevent

the

spread of

Temephos resistance

by reinvasion of ^the local, resistant, vector

^population

into the

East

of the

^OCP area which

is still free of resistance. Larviciding

could

therefore not be interrupted during the

reinvasion

period

from May to

July, but it

was esteemed

that local control

could be

safely interrupted

^from

August

to February.

The study was

therefore

designed

as

follows:

-

^Vector

control

was

interrupted

from August 1987

to half

February 1988 in

the

Asubende focus

to allow a local

population

of

S.damnosum

s.s.

and/or S.sirbanum

to establish itself

and

build

up

to

an

equilibrium Ievel. This equilibrium

was reached

early

September 1987 and ^was maintained

tilI half

February when

]arviciding

recommenced.

In

October 1987

ivermectin

was administered

to the total population

in

the area,

which

is a

probable source

of transnission

and

eligible for

treatment.

-

^The

^treated

population was monitored

for

adverse

reactions following

treatment according

to a

monitoring procedure designed

for the

study.

This

included monitoring

of the total treated population for

serious adverse

reactions during the first

72 hours and monitoring

of

the populuation

of in villages with a resident

monitoring tean

for all

adverse

reactions during the

72 hour

period.

A selected population

r+ilI

be followed-up

after 3, 6

and 12 months.

Intensified

entomological

evaluation

was undertaken from 1 September 1987

to

11 February 1988, and

the findings on infectivity levels in

the

vector

before and

after

ivermectin treatment

in

1987 were compared with

the historical results for the

same periods

of the

^year between 1978 and 1985.

Uo

F E

6(D@

ozo=

ro=N (9

oo l

=\

;o_

a(J o Fi ure 3

(l,c oN o,c

E

oo,

c

C' o, E c,

N N

UJ

E.

o :f F

U)

t-tJ

o

z

UJ(D

f a

I0 5

oI :I

H \

iJ F

o o o

o

r,o.

\

\

o

Do

fqt urF

z

H H

H

oE Eo :}

t

E

\a'

Eo

2

H

J

H

o0

H

a

I

a

H

/

9

ts

I

\

\

t I

\

\

\

\

\

\

b o

9

IV.

^{MASS TREATMENT} WITH IVERMECTIN.

IV.1.

Organization

of ivernectin treatuent

and

nonitoring

^g.;[ adverse

reactions

.

The connunity

trial in

Asubende was undertaken as

a collaborative effort of the

OCP' OCRC and

the

Ghanaian

Ministry of Health. Responsibilities

were

assigned

to take

advantage

of the different strengths of the institutions participating in the trial.

The OCP personnel was mostly

involved in organisation,

drug

distribution

and managenent

of information

collected

whereas

the

Ghanaian personnel was

nainly active in the nonitoring of

adverse

events.

Guidelines

for

monitoring and drug

distribution

were prepared and

given to all participants to the trial in order to

standardise

the

procedures.

For

the

same purpose

all

^personnel was

briefed a

few days

before the start of field activities.

A major

effort

^was undertaken

to

ensure community

participation.

Local

authorities

were

inforned

through

official

channels

of the

purpose and nature

of the work.

Two teams were

sent a

week

in

advance

to mobilise the

^population and complete

the

census

for the najority of villages

included

in the trial.

The youth

organisation of the villages

was mobilised

for the

census

ind later

on helped

in the

drug

distribution.

The town

of

Prang was chosen as the headquarters

of the operation.

The

trial

area was

divided into 7

sectors, each assigned

to a

team composed by

a

medical

officer,

&

nurse, a

census

clerk

and an

assistant . Monitoring for the required

72

hrs

was

carried out

by

nurses.

Two types

of nonitoring

were used, one assured by

a

nurse

living in the village for the required period of tine

and

the other

performed by a

mobile nurse

that visited

nore than

a village at least

once

a day.

The

decision

whether monitoring should be mobile

or resident

was nade

after

taking

into

account

the level of endenicity

and

the

leve1

of dispersion of the trial population.

The monitoring nurses were supervised by

nedical officersr. AIl

cases

of

severe events were reviewed by

the

medical

officers

and

if

needed

referred to the field hospital in

^Prang.

IV.2.

Census

oopulation. treatnent

coveraEe and

ivernectin

dosage.

For

analysis

purposes,

the trial

&rea was devided

into 9

zones according

to the level of

endemicity and

the type of nonitoring done. This division is

shown

in figure 3

and

recurs in a

nunber

of

tables.

Throughout

the trial area,

251379 people were included

in the

census

of

which 14'488 were

treated.

The cover&ge was

rather uniforn in the g

zones

with the

exception

of

zone

IX

where

only skin snip positive

people were

treated.

As expected,

the best

coverage was obtained

in snall isolated villages.

The average coverage, excluding zone

IX,

was 61.32 ^(see

table

²⁾

and 74,D(

of the population

above

the

age

of 5

^{years (see}

table 3).

^The

coverage was

lowest in the

age group 20-29 years

of

age

for both

males and

females.

An age

of less

than

5

^years was

the

most

frequent

cause

of

no-treatment (45,2%) follor.red

by failure to

^present

at the

treatment post

(33.32).

The

other

reasons

for

no treatment were

less

important

for

^coverage

(see

table 4).

During

the trial,

two

criteria

were used

for the

exclusion of

children

from

treatment, i.e.

an age

of less than 5

years

or a

weight below 15

kg.

The age

criterion

was

specified by the

manufacturer

of the

drug and the

latter

was included because

in

West

African villages

age

is often

estimated

while

treatment

of

people below 15 kg

of

weight

will

cause

overdosing.

Table

5 indicates that

4.62

of the

chiLdren below 12 years

of

^age would have been

overdosed

if the

second

criterion

would

not

have been used

during the trial.

If in future the ninimal

age

for

treatment

wiII

be lowered,

this situation

nay

worsen and,

a

system based on weight

is operationally preferable.

The average dose

of drug intake by

&ge group

is

shown

in table 5.

People below

the

age

of

20 years received an average dose

very close to the ideal

150 mcg/kg whereas

the adults

received approximately 15 mcg,/kg

more.

Over

aII the

mean dosage was 159.5 mcg/kg (see

table 6). At the

end

of the trials

^planned

for

1988,

page 10

the

dose schcrdule

could

be reviewed

if the

adverse

reactions

reported

wiII justify _a

concern

for higlr

dosages, and an

alternative

schedule

in

^{whictr thc}

minimum and raxinum dosagc remains 100 and 200 ncg/kg

is ^given in table

7b.

If this altcrnativc

schedulc would have been used,

the

average dose

in

adults would have been reduced from 165 mcg/kg

to

al;out 125

ncg/kg, as is

shown in

table

8.

Table

2:

Census population and coverage

of ivermectin

treatment

per

zone

Treated

with

ivermectin

Zone

Description Popu ^CensusIat ion ^No. z

I.

HoIo-endemic

villages II. First Iine

North

III. First

Line South

IV.

Prang

V.

Abease

VI.

Main ^Road

Vi

I. Third line VIII.

Pranbo area

IX.

West

of

^Abease

898 2897 1411 5079 1952 3919

13 71 504 6 28 16

573 1819 1060 3348

1 168 22L6 1007 2630 667

63.

I

62.

I

75. 1

65.

I

59.8 56. ⁵ 73. ⁵ 52.

I

23.7

Total

zone

I to VIII

Total

excluding zone

IX

where

only skin snip positives

were

treated with ivernectin

25389 2257 3

1 4488 57. 1

13821 61.2

- .

_Table

3:

^CoveraBe

of ivermectin

treatmetrt by age and sex

MaIes Females TotaI

Age in

years Treated

Census (as Z)

T reated Census (as %)

'I reated (-lcnsus (as % )

0-4 5-9 10-19 20-29 30-39 40-49 50-59

60+

Missing

1970 1924 2690 1612 I 306 867 514 574 33

1975

t824

2 506 1800

1 280 789 451 433 25

0.0 74.4

'74 '7

62.7 68. 4

74.9 77.8 75. B

52.0

394 5

37 48

5 196

34t2

2586 1656 965 100 7

58

0.0 75.4 77.3 66. ⁶

7 2.3 76.3 79.1 78.4 36,2 0.0

76. 4

80. ⁷ 71.0 76. ¹ 77.5 80. ² 80. 3

24.2

Age

5

^yrs and above

TabIe

4.

Re&sons

for

no treaLment (exciudrng liest.-Abease) TotaI

Reason

1 1490 9520

63. 8

77.0

1 1083 9108

58. ⁶

i1.3

61.2 71.2

Numbe r

not

treated

2257 3

18628

Pe rcentage

of

Lotai

not

^treated

Age below

5

^years

I{e

ight

^{be Iow 15 kgs}

Pregnant

First

nonth

of

Iactati<-rn Severe

illness

CNS disease

J aund i ce

Refused treatment

Examined and othe'r ^reasr,rtr Not speci

fied

ln village but

noL examined

Absent

for less

than

1

^year

:i94 5

191 358

45.

i

22 4.r 0.9 1.0 1.4

0 .'2

0.5 1.9 9.5 13.8 19.4 79

89

'l ?(

14

t'2 170

83i

1211 169 5

TotaI ^{87 50 100.0}

Page

i2

Table

5.

Bodywelght

of chl'ldrcn

bclow

the

age

of

^{12 years.}

Hetght

in

kllograms

Chi

ldren

with

weight <

15 k9

Age in

years x

Number

of

chl ldren

examl ned ],lean S.D no.

5 6 7

I

9 10 11

582 736 628 703 484 686 370

16. 9

18. 7

20. 5

22.4 24.4 26. ⁵ 21.9

6 8 5 4

1

80 57 04 87 2 3 4 4 5 5 5

97 16. 7

8.2 2.5 1.1 1.0 0.6 0.3

60

09 87 72

Total

⁴¹⁸⁹ 22.1 5. E5 191 4.6

Table

6.

^Number

of tab'lets

and mean dosage

of

ivermectin by ^age.

Number

of tablets

^{given Dosage}

of

^ivermectin

in

mcg/kg bodyweight Age in

years

Number

of

persons

treated 0.5

1

^{1.5 2 Mean SD}

5-9

10

-

¹⁹

20-29 30-39 40-49 50-59

60+

Missing

2930 4216 2419

1 956 1317 799 829 22

2805

1 300 10 2

1

2

3 10

116

1 800 245 198 174 134 180 3

1 075

1 866

1 469 941 529 544

I

0 41 298 287 201 134 102

1

152.7 155. 3

164.9 164.4 163. ⁵ 164.6 165. 3

160.9

25. ⁶ 29. 0

't7.0

17 .4

17 .2 17.8 17.9

27 .8

9

Total ¹

4488

⁴¹

33 2850 6441

^{1 064}

16706

tablets

^used

1.15

tablets ^per

Person on average

1 59.

5

^23.0

TableT

a.

Recommended ivermectrn dosaqe schedule

M i n i

mum

l{ax i

mum

no.

of

Max.imum we'i

ght

we i

ght

tab ^I

ets

dosage

Mi nimum dosage 't5

30 45 65

200 200 200 185 29

44 64 120

0 5

1

5 2

103 136 '141 100

1

Table 7,b.

Alternative ivermectin

dosage schedu'le

M i n i

mum

l.iax i

mum

no.

of

Max i mum

wei

ght

wei

ght

tabl

ets

dosage

M i n'imum dosage

15 30 50 75

29 49 74 120

0 5

1

5 2

200 200 180 160

103 122 122 100

Table 8

.

Mean dosage

of ivermectin

obta'ined

with

recormended schedule and mean dosage which would have been obtained

if alternat'ive

schedule had been used.

Dosage

of

ivermect'in

in

mcg/kg bodyweight Age in

years

No. treated w'ith proper record

of

bodywe'i ght

Using recommended

schedu'le

(table

_7a) ^Using

alternative

schedule

(table

_7b)

Mean SD Mean SD

5-9

10

-

¹⁹

20-29 30-39 40-49 50-59

60+

tlissing

2858 4088 2346

1 900

1 289 783 816 22

152.7 155.3 164. 9

164.4 163. 5

164. 6

165.3 160.9

25. ⁶ 29. 0

17.0

17 .4

17 .2 17.8 17.9

27 .8

153.1

1 42.3 124.9 125.5 126.4 126.

I

128.7 145.3

25. 6

28. 6

15.

I

15.9 16. ¹ 15.6 17.7 32.7

Tota I 1 4102

159.5

23.0

136.3

22.4

page 14

IV.3. Effect

on

skin microfilarial

loads

in the

holo-endenic ^v

iIl

s.

The

highest microfilarial

loads were found

in the first line villages

which

are situated north of the river

and

close to the

Asubende catching

point. It

concerns

the villages of

^Asubende

proper, together with five

satellite settlements,

and

the villages of

Faomang and Niampe. These

villages are referred to in the

present

report

as

the

holo-endemic

villages.

No skin

snip

data

are available for the first line villages

located South

of this

^part

of the river, but it is likely that the

leveL

of

endemicity

there

^was

just

as hi gh.

The

results of a skin snip

survey which was undertaken

in

October 19BB as

part of a

complete pre-treatment ophthalmological examination

of

these

holo-endemic

villages, are given in table 9. It

can be seen

that the level

of endemicity

is

extremely

high in

those

villages: the

standardized prevalence of

microfilariae in the skin snip (mfs) is

85.4%,

a

value which

is hardly

ever found

for

West-African savanna

villages.

The CMFL

is

as

high

as 61.9 mfs and

reaches 78.6 mfs

in

males, and

this indicates that there is a very high risk of

severe

ocular }esions

and blindness.

This

^grave epidemiological

situation

had completely changed

after

the

distribution of ivermectin.

^The

effect of the

drug on

microfilarial

loads

in

those

treated is

shown

in figure 4 for

415

villagers

^who had

a skin snip

taken

during the pre-treatnent

survey

in

^{October 1987 as}

well

as

during a

follow-up survey

in

^December

1987.

During

the

pre-treatment survey as many 61%

of

these viJ"Iagers had

a skin snip load in

excess

of

64 mfs and were

therefore at

high

risk of

developing onchocercal

pathology. After

treatment 92,5%

of the

⁴¹⁵

villages

had

a skin snip

load

of less

than

8 mfs, while

45% were even skin

snip negative.

However,

in

about 5Z

of the treated

^persons

there

was less than 75%

reduction in the microfilarial load

and

a

few had

still

more than 64

mfs

during the follow-up

survey.

The average

reduction in skin microfilarial

loads

by

age

is

shown in

figure 5 for a cohort of

151

villagers

^who have undergone

4 skin

snip examinations: two pre-treatment examinations

during

1987 and two

post-treatment examinations

after 8

and 16 weeks

respectively.

^The

pre-treatment

results

show a.

very similar age-specific pattern

even though the

results for April

1987 a.re

a bit

lower than those

for

^October

1987. After ivermectin

treatment

the

^geometric mean mfs

load

had

faIlen by

^97% and the percentage

reduction

^was

the

same

for aII

age

groups.

The mean loads

for

February 1988 show

a

marginal increase and

also this

increase appears

to

^be

independent

of age.

Less spectacular

are the results for the

prevalence of

infection

as shown

in figure 6.

The prevalence, which was already between 70%

and 80%

in the 5-9

^year age group, has

in

^December 1987

fallen

^{by about 45% in}

nerarly

aIl

age

groups.

However,

in

February

the

prevalence had bounced bacli

to

87%

of its original value.

These

results for the

changes

in the

^prevalence and

intensity of infection are

summ&rized

in figure 7

where

the

immediate

pre-treatment survey

is

taken as

a

reference and

aII results are

expressed ^as

a

percentage

of the

corresponding reference

values. it is

important

to

note

that the

observed increase between

the

two post-treatment surveys

in

the geometric mean

microfilarial load

from 3%

to

^10%

of its

pre-treatment value, and

the

increase

in the

prevalence from 55%

to close to

^90%

of its original

value, is not reflected in the

errtomological data on

the infection

IeveLs in Lhe vecLor whir-'h

did not

^show an;' increase

over this ^period

^(see

also

chapter IV).