Malaria Prevention for Long-term Travellers · Afghanistan P. vivax attack rate 5.2/100 Leutscher et al. 2003 Peace Corps, Madagascar 16% reported malaria Ross et Hodge ... Variation

PS/VER/LTT/9-2009-1

Malaria Prevention forLong-term Travellers

Patricia Schlagenhauf

PS/VER/LTT/9-2009-2

Risk?Risk?

PS/VER/LTT/9-2009-3

Riverain Exploration in Africa*

Mungo Park - Niger (1805) Captain Tuckey - Congo (1816) Clapperton - Niger (1827) Lander - Niger (1830) MacGregor Laird - Niger (1832-34) Captain Trotter - Niger (1841)

Mortality for the combined expeditionswas 49% (138 dead/281) (Mungo Park-91%)*Gelfand M (1964) Rivers of death in Africa, Oxford University Press, London

PS/VER/LTT/9-2009-4

RISK of malaria in long-termtravellers - GeoSentinel

Long-term > 6 months Compared to short-term travellers:*

P. falciparum (OR=1.5, CI: 1.25-1.79)P. vivax (OR=2.44, CI:1.89-3.14)

Depends on destination AFRICA season,exposure,preventive measures, sex Type of travel - expat., backpacker, VFR

*Chen L et al. Analysis of long-term travellers, in press EID 2009

PS/VER/LTT/9-2009-5

Malaria risk data forlong-term travellersAuthor Traveller Type Malaria Risk

Jute et Toovey2007

Expat. miners inMali

22% contracted malariadespite prophylaxis

Kotwall et al. US soldiers,Afghanistan

P. vivax attack rate5.2/100

Leutscher et al.2003

Peace Corps,Madagascar

16% reported malaria

Ross et Hodge2000

Expat. miners inZambia

82% had a malariadiagnosis

Peppiatt et Byass1991

UK missionaries 87.3 malaria cases per1000 persons per year.

PS/VER/LTT/9-2009-6

The need to balance riskand benefit

High risk areas

Adherence

PS/VER/LTT/9-2009-7

The need to balance riskand benefit

High risk areas

Adherence

„The statistical probability of being infected by sporozoites increases to almost 100% if the stay in in the malaria endemic area >4 weeks assuming 10 bites per night and 1% of bites being infective......“

Knobloch J , JTM 2004

PS/VER/LTT/9-2009-8Chen, Wilson, Schlagenhauf. JAMA 2006

Long Term Travel and Malaria

High Risk Malaria Areas Moderate Limited Risk Areas Low Risk Areas

Concise advice regarding mosquito bite prevention

Continuous Chemoprophylaxis

Continuous or Seasonal Chemoprophylaxis

Stand-by Emergency Self-treatment

Detailed written and oral advice on recognition and treatment of malaria symptoms.Self-diagnosis and treatment for remote areas. Identification of nearest MD for malaria emergencies.

PS/VER/LTT/9-2009-9

Personal protection measuresPPMs for long term travel –where’s the evidence?

PS/VER/LTT/9-2009-10

Location Long term traveller InterventionLahore, India,1925

British Infantry pre-proofing 549/1000post-proofing 45/1000

India, 1927 British Infantry pre-proofing 613/1000post-proofing 58/1000

Honduras, 1926 Workers pre-proofing 29.1%post-proofing 6.6%

Mosquito proofing

Keiser et al. Lancet Infect Dis Nov 2005


„I myself have been infected with malaria only once in spite of 32 years service inthe tropics. I attritribute this good fortune to my scrupulous use of the bed net...“

Mosquito nets offer excellentprotection during the night

„ITN’s are highly effective” – Lengeler 2005, Cochrane Review


Personal protection measures PPMsAre effective if used correctly!

Lillie TH et al. J Med Entomol 1988; 25:475–478

In one studyIn one studybiting ratebiting ratewas reducedwas reducedfrom 1000from 1000bites to 1 bitebites to 1 biteper hour *per hour *


Evidence of efficacy ofEvidence of efficacy ofpersonal protection measures*personal protection measures*

Study Measure OutcomeKeiser et al. 2005Systematic review

Reduce vectorhabitats

Reduced risk ratio ofmalaria by 80-88%

Lengeler 2004Systematic review

Insecticide treatedbed nets

Reduced malaria incidenceby 50-62%

Soto et al 1995Controlled double-blindstudy

Permethrinimpregnated clothing

Reduced malaria incidencein soldiers

Durrheim/Govere 2002Observational study

Application of 15%DEET to ankles andfeet

Successful in reducingbites of An. arabiensis

Govere et al 2001Human bait study

Use of DEET inhuman bait

Reduced bites of An.Arabiensis by 69%

* Chen, Wilson, Schlagenhauf JAMA 2006


Repellents – pros and cons

Repellent Advantages DisadvantagesDEET Widely used and tested, effective

20% protects for >5hours*May damage fabrics andplastics

Bayrepel®PicaridinKBR 3023

19.2% preparation similarprotection to DEETbest against An gambiae. **Less irritating than DEET.

Inter-individual variation

EBAAPIR3535

Mean protection 23minutes*Good cosmetic properties

Variation in efficacy

PMDEucalyptuscitriodora

96%protection for up to 4 hoursPlant based repellentWell tolerated

Inter-individual variation

Natural Oils ”Bio” – high acceptance (very) short protection duration


Mefloquine unlimited, good dataAtovaquone/proguanil US unlimited/Europe 28 Days

Doxycycline 6 months (?)Chloroquine/proguanil unlimited -limited usePrimaquine few long term data

Mefloquine250 mg WEEKLY

Atovaquone/proguanil250mg/100mg daily

Doxycycline100mg daily

Priority Antimalarial

Chloroquine 300mg base weekly+ proguanil 200mg daily Primaquine (30mg base) daily

* * *

Chemoprophylaxis Choices


TRAVEL forTRAVEL for6 months6 months-2 -1 +1 +2 +3 +4 weeks

188 daily doses ofatovaquone / proguanil

29 weekly doses of mefloquine

211 daily doses of doxycycline

Compliance???

„The compliance is inverselyproportional to the complexity of theprescription“ (Haynes & Sackett 1976)


Take thine malaria medication

Group Adherence ReferencePeace corps, Africa 90% Lobel 1993

American missions, Africa 72% Lange 1987

Missionaries in Zaire 62%(58% missed doses)

Burdon 1998

UK mine workers, Ghana 51% Fegan 1993

Missionary children, Africa 19% Dwelle 1995



Experience with long-termuse of chemoprophylaxisDoxycycline Australian military. Withdrawal rates due to

AE 0.6-1.7%Expected AE: photosensitivity, Candidasuperinfection, GIT (use hydrate)

Atovaquone/proguanil

long term use in Dutch travellers (2-4%withdrawal due to AE),Danishsoldiers,Indonesian transmigrants

Primaquine few data. Some experience in Javanesetransmigrants. G6PDH

Mefloquine well tolerated long-term if initially no AE.Good data.


Mefloquine plasma levels reached during long-term malaria chemoprophylaxis*

steady state, no accumulation

* Schlagenhauf P 1995


T-Sc

ore

of th

e M

EAN

Norm=50

*

*JOURNAL OF TRAVEL MEDICINE 2009


T-Sc

ore

of th

e M

EAN

Norm=50


Seasonal prophylaxis?Seasonal prophylaxis?

• Little to no data available

• Unpredictable conditions in many areas

• Possibility for Namibia, Botswana, South Africa

• Seek local advice after 6 months


Namibia BotswanaHigh risk: Nov - June High risk: Nov - June

Cave! Transmission season shifts are possible!


Pf: P. falciparum, Pv: P. vivax,

Po: P. ovale, Pm: P. malariae

Pf(Po, Pm, Pv)

Pv

PvPf/Pv

P. vivax prophylaxis during longterm-travel – is there a strategy?

Pv(Pf)

Pv(Pf)


Long-term travel in P.vivax areas

Late onset malaria despite prophylaxis eg.Soldiers returning from Afghanistan

P.vivax areas - terminal prophylaxis withprimaquine is required

Primaquine prophylaxis not reg. in Europe

Cave G6PD deficiency


Malaria in Afghanistan


P. vivax attack rate 5.2/100 !

Late onset - mean 233 days post travel

Adherence: 52% weekly prophylaxis41% terminal prophylaxis29% insect repellents

P. vivax in long term travel


Primary infection

Late infection(Relapse)

Hypnozoite

Tissue schizonte

Tissue schizonte

~2 weeks

~2 weeks

Sporozoites

Dormant period-several weeks to several years


P.vivax North Korean strain

Sporozoites

14 d Blood- primary acute infection

Hypnozoite8-9 mo. Blood-late acute infection (R)

16-18 mo Blood-late acute infection (R)

P.vivax Tropical strain

Sporozoites

14d Blood- primary acute infection

Hypnozoite

1m blood relapse2m3m4m5m6m 7m

blood relapseblood relapseblood relapseblood relapseblood relapseblood relapse

P. vivax Relapse Patterns

PART

PART

Current guidelines for long term travellers do not address the issue of presumptive anti-relapse treatment (PART)


Monkey malaria may be an issuefor long-term travellers in SE Asia


StrategyAntimosquito measures +Stand By Emergency Treatment

MalariaProphy-laxis AE

LOW RISK TRAVELLERS


StrategyAntimosquito measures +Stand By Emergency Treatment

MalariaProphy-laxis AE

LOW RISK TRAVELLERS

„self treatment is the use of anti-malarialdrugs when malaria is suspected andprompt MD attention is unavailable within

24 hours“ (Definition WHO 2004)


* Preferred - effective, well tolerated

Range of Medications for StandBy Emergency Self Treatment

Medication Adult DoseMefloquine 25 mg base/kg (6 Tablets)

in one day

Chloroquine 25 mg base/kg (10 Tablets)over 3 days

Quinine 8 mg base/kg po (42 Tablets)3 x daily for 7 days

Arthemether/Lumefantrine (20mg/120mg)

Riamet®*24 Tablets over 3 days

Atovaquone/Proguanil (250mg/100mg)

Malarone®*12 Tablets over 3 days


Chloroquine as SBET

Low risk areas according to Swiss/German guidelines–

CT

COMORESSAO TOMÉ & PRINCIPE SEYCHELLES

MAURITIUS

CAPE VERDE Goa

MALDIVES

PULAU LOMBOK

BALI FLORESSUMBAWA

HONG KONG

MACAO

BRUNEI

SINGAPORE

MalukuMadras

TakTrat

VANUATU bis Tanna

Salomonen

© SAGRM

C T–

Schw. Arbeitsgruppe für Reisemedizin

The world according to Swiss/German guidelines


new! India


*

* Artemisinin resistance on the Thai/Cambodian border. Dondorp NEJM 2009


*Trachsler et al.1999, Funk et al. 1999, Jelinek et al. 1999, Behrens&Whitty 2000

Use of rapid malaria tests bytravellers

68-91%* successful

false negatives

problems at lowparasitemias (<0.1%)

Could be useful forlong-term travellers??


Jelinek, Amsler, Grobusch. Lancet 1999

Reasons travellers get invalidresults with rapid tests

Unable to draw blood 22/31 (71%)

Unable to place blood droplet on kit (26%)

Did not wait for the recommended 8 min(39%)

Unable to identify bands showing results(58%)

Unable to interpret the result (87%)


„Malaria is our enemynumber one. Every Sundaywe swallow quinine tabletsso bitter your tongue wantsto turn itself inside out like asalted slug. But Mrs.Underdown warned us that,pills or no pills, too manymosquito bites could stillovertake the quinine in ourblood and spell ourdoom......“

Leah, missionary child, Congo 1950‘s

Long-term travel with children


Anti-malarialchemoprophylaxis for children

Anti-malarial Chemoprophylaxis DOSING

Atovaquone/proguanil

*>5kg CDC>11 kg Europe, manufacturer

-DAILY-Pediatric tablets

Chloroquine** All ages and weights 5mg base/kgWEEKLY

Doxycycline Children> 8years 1.5mg salt/kg DAILY

Mefloquine >5kg 5mg/kgWEEKLY

Primaquine Children>4 years WHOCDC specifies no lower agelimit

0.5mg/kg baseDAILY

* new ** limited use due to widespread resistance


Stand-by emergency treatmentSBET of infants and small children

Pf malaria is an emergency. Identify MDfacility BEFORE travel

Give exact dosages of malaria treatmentsfor all members of the family

New! Coartem® dispersible (Artequin®,suppository-Plasmotrim®)

Early symptoms often atypical-seek MD

Emergency - reduce fever, initiate therapy


Long-term travel inpregnancy/antimalarials?

Antimalarialsfor

Prophylaxis** in

Pregnancy

AtovaquoneProguanil

Mefloquine

Doxycycline

Chloroquine

Primaquine

Contraindicated

Allowed 1*, 2, 3trimester

Contraindicated

Allowed 1, 2, 3 trimester

Contraindicated

* CDC (high risk only)**For multi-drug resistant Pf areas there is NO SAFE chemoprophylaxis for pregnant women


Counterfeit drugs - a global problem



Fake Facts*Fake Facts*- Cambodia, 71% fake arrtesunate- Cambodia, 71% fake arrtesunate- SE Asia, 38-73% fake artesunate- SE Asia, 38-73% fake artesunate

- Nigeria, 42% - Nigeria, 42% „„inadequateinadequate““ malaria meds malaria meds- Fake diagnostic tests - Fake diagnostic tests

* Newton 2008 in * Newton 2008 in „„TravelersTravelers`Malaria`Malaria““ (ed. Schlagenhauf) (ed. Schlagenhauf)



Fake Facts*Fake Facts*- Cambodia, 71% fake arrtesunate- Cambodia, 71% fake arrtesunate- SE Asia, 38-73% fake artesunate- SE Asia, 38-73% fake artesunate

- Nigeria, 42% - Nigeria, 42% „„inadequateinadequate““ malaria meds malaria meds- Fake diagnostic tests - Fake diagnostic tests

* Newton 2008 in * Newton 2008 in „„TravelersTravelers`Malaria`Malaria““ (ed. Schlagenhauf) (ed. Schlagenhauf)

Long-term travellers should Long-term travellers should bring along adequate bring along adequate supplies of medicationsupplies of medication


Knowledge of risk,season, vector

ESSENTIAL

Protection againstmosquito bites

ESSENTIAL

Stand-by emergencyself treatment

Remote and low risk areaseg S. America and Asia

Seasonal prophylaxis Limited applicability

Continuous propylaxis High risk areas in Africa,PNG

Rapid malaria tests Remote areas. TRAINING!

Summary of anti-malariastrategies for long-term travel


Mille grazie!

Malaria Prevention for Long-term Travellers · Afghanistan P. vivax attack rate 5.2/100 Leutscher et al. 2003 Peace Corps, Madagascar 16% reported malaria Ross et Hodge ... Variation

Documents