Chapter 5.3 – Malaria issues in special hosts - Long-term traveller or expatriate: Canadian recommendations for the prevention and treatment of malaria

An Advisory Committee Statement (ACS) from the
Committee to Advise on Tropical Medicine and Travel (CATMAT)

Preamble

The Committee to Advise on Tropical Medicine and Travel (CATMAT) provides the Public Health Agency of Canada (PHAC) with ongoing and timely medical, scientific, and public health advice relating to tropical infectious disease and health risks associated with international travel. PHAC acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and medical practices, and is disseminating this document for information purposes to both travellers and the medical community caring for travellers.

Persons administering or using drugs, vaccines, or other products should also be aware of the contents of the product monograph(s) or other similarly approved standards or instructions for use. Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) or other similarly approved standards or instructions for use by the licensed manufacturer(s). Manufacturers have sought approval and provided evidence as to the safety and efficacy of their products only when used in accordance with the product monographs or other similarly approved standards or instructions for use.

Chapter 5: Malaria issues in special hosts

5.3 Prevention in special hosts—long term or expatriate

Preventing malaria in the long term traveller or expatriate

The particular concerns that relate to preventing malaria in long-term travellers (those who travel for more than one month) and expatriates include: safety of chemoprophylactic drugs and fear of toxic effects with prolonged use of medication; cost of long-term medication; use of locally procured drugs that may be counterfeit; conflicting counsel about appropriate chemoprophylaxis and self- treatment; and lack of adherence to chemoprophylaxis and personal protective measures (PPM).

Modern prevention strategies have had a significant positive impact on the risk of malaria-related mortality in long-term expatriates. Mortality was reported to be as high as 60% among missionaries in West Africa during the 20th centuryReference 1. However, developing unique, evidence-based guidelines for the long-term traveller or expatriate has been limited by a lack of medical literature in this area, as well as the variability in risk based on location, occupation, lifestyle and activitiesReference 2. The risk of malaria associated with location, or the entomological inoculation rate, may vary depending on the season, as well as whether the location is rural, peri-urban or urban.

The advice of health care providers may compete with the opinions of travellers who assume that their personal experience with drug-related adverse events is representative of the general populationReference 3. Some researchers have observed that the incidence of malaria may be greater among veteran expatriates than among their less experienced counterparts. The veteran expatriates may have unreasonable confidence in their clinical self-diagnosisReference 4 compounded by false-positive laboratory errorsReference 5. The use of counterfeit drugs can also lead to drug resistance or, more immediately, treatment failures. Users may then generalize the resultant failure of response of a specific medication to all malaria medicationsReference 6.

Adverse events

A survey of over 2,700 Peace Corps volunteers found that 62% reported one or more adverse events, with 9% reporting serious adverse events and 23% changing malaria prophylaxis due to adverse eventsReference 7.

There is no evidence to suggest that long-term use of therapies currently recommended for short-stay travellers results in additional risk of severe adverse events. Chloroquine may be an exception; the risk of chloroquine retinopathy requires an ophthalmologic exam at least every two years for travellers using chloroquine long-termReference 8. However, this drug is seldom indicated because of extensive drug resistance. Although the data supporting long-term use of doxycycline for chemoprophylaxis are limited, the drug and the related minocycline is in use for extended periods of time for other indicationsReference 9.

Mefloquine tolerance improves over time, possibly associated with the relatively early onset of adverse events experienced by those who use mefloquine for prophylaxisReference 5. Consequently, there does not appear to be increased risk with long-term useReference 10. Although there are few data on prolonged use of atovaquone-proguanil, the individual components have been used for extended periods of timeReference 8.

Current malaria prevention practive among expatriates

Malaria chemoprophylaxis use in expatriates is suboptimal. Only 69% of expatriate households in Nigeria appropriately picked up their chemoprophylaxis from the pharmacy, and among those that did, 58% were nonadherent, resulting in an overall nonadherence rate of 61%Reference 11. A study of expatriates in western Ghana found that duration of stay was inversely proportional to adherence to malaria chemoprophylaxis; 80% of those who had been in western Ghana for three months or less were taking malaria chemoprophylaxis, compared to none of the workers who had been there for over a yearReference 12. A review of health behaviours among expatriate workers for the International Committee of the Red Cross reported 65% adherence to recommended malaria chemoprophylaxisReference 13. Finally, a survey of expatriate health care workers in Equatorial Guinea found that only 31% adhered to their malaria chemoprophylaxis regimenReference 14.

Data collected from deployed military troops also suggest poor adherence to recommended malaria chemoprophylaxis. Of over 1,000 French soldiers assigned to missions in sub-Saharan Africa, only 61% reported taking their chemoprophylaxisReference 15. A more recent report only 45% compliance with malaria prophylaxis among 575 French soldiers stationed in Ivory CoastReference 16. This is comparable to the outcome of an anonymous, post-deployment survey of United States Army Rangers returned from Afghanistan, where the self-reported compliance rate was 52% for weekly chemoprophylaxis, 41% for terminal (post-deployment) chemoprophylaxis, 31% for both weekly and terminal chemoprophylaxis. In this group 82% reported treating uniforms with permethrin, and 29% for the application of insect repellentReference 17.

Support for established guidelines

In general, guidelines for preventing malaria in long-term travellers or expatriates should be very similar to standard recommendations for the short-term traveller, though cost may limit the use of more expensive drugs such as atovaquone-proguanil. However, given how poorly long-term travellers tend to adhere to malaria chemoprophylaxis, pre-travel advice regarding malaria precautions should also include a description of malaria symptoms and emphasis on the need for early diagnosis and treatment; a discussion of the need to develop a plan for accessing competent medical care in the event of illness; detailed advice regarding PPM (see Chapter 3); the use of standby emergency therapy (self-treatment), if applicable; and the possibility of counterfeit malaria drugs procured locallyReference 10.

Data on the incidence of malaria in long-term travellers are limited; also limited are data on the effectiveness and tolerance of currently recommended regimens. Studies conducted in chloroquine- resistant regions consistently demonstrate that mefloquine is more effective than chloroquine and proguanil and its long-term use and that it is well toleratedReference 5, Reference 18, Reference 19, Reference 20. Better knowledge about malaria seems to benefit compliance: a preventive malaria program for nonimmune expatriates working in malaria-endemic areas resulted in significant increase in knowledge about malaria and improved practices including greater adherence to chemoprophylaxisReference 19. Another program that included instruction on Canadian guidelines, PPM and self-treatment with self-administered positive rapid diagnostic tests was instituted for a cohort of expatriates in Ghana, among whom the incidence of malaria ranged from 1/50 to 1/25 per month between 1993 and 1999 (2%–4%). Subsequent surveillance data indicated that the monthly incidence of malaria decreased from 4/1,000 in 2000 to 1.7/1,000 in 2002 (0.4%–0.17%) (unpublished data, K. Gamble).

Insecxticide treated bed nets

CATMAT recommends that all travellers to malaria-endemic regions use insecticide-treated bed nets as part of their PPM (see Chapter 3). For the majority of travellers, conventional insecticide-treated bednets provide sufficiently long-lasting protection. However, long-term travellers face additional challenges: the insecticide that is in most nets starts to lose its effect after 6 months. Thus, where travel to a malaria-endemic area is frequent and/or is expected to be for 6 months or longer, conventionally treated bed nets are inadequate and long-lasting insecticide- treated nets would be preferableReference 21. Currently there are no Canadian long-lasting insecticide- treated nets registrations, nor is there a specific policy that permits their sale in Canada for use abroad; in addition, liquid permethrin (an insecticide used to treat bed nets) is not available in Canada. Nevertheless, insecticide-treated bed nets can be obtained from some Canadian travel health clinics and other domestic and international suppliersReference 21.

Long-term travellers also need to know about seasonal changes in weather that affect malaria risk and loss of effect of the insecticide-impregnating bed nets. This means that the start of rainy seasons requires the renewal of this insecticide in bed nets.

Rapid diagnostic tests

Without adequate training of laboratory staff, the usefulness of rapid diagnostic tests (RDTs) may  be no better than that shown in the general travel populationReference 22, Reference 23 (see Chapter 6 for information on malaria diagnosis and RDTs). However, expatriates are often part of a reasonably stable community, which allows for the training of key members on the use of RDTs and the administration of appropriate self-treatment. Caution is warranted, however; there are few data from controlled studies on the use of RDTs in the long-term traveller or expatriate populations. An evaluation of a preventive malaria program for expatriates in malaria-endemic areas, which included RDTs and standby treatment, found that 15% of participants had difficulty performing the RDTs and 22% used standby treatment despite having a negative RDTReference 24.

Counterfeit drugs

The production, distribution and sale of counterfeit antimalarial, antiretroviral and other medications are widespread throughout many parts of Asia and AfricaReference 25, Reference 26, Reference 27. One-third to one-half of artesunate tablets in Southeast Asia have been found to have no active ingredientReference 25. Many expatriates buy their antimalarial drugs over the counter, and they do not have the ability to evaluate the authenticity of these drugs. Unfortunately, simply encouraging expatriates and long-term travellers to purchase brand names may be insufficientReference 25, Reference 26, Reference 27.

The counterfeit drug problem is especially important for long-term travellers because they are dependent on local pharmacies for renewal of their antimalarial chemoprophylaxis prescriptions and often for standby malaria self-treatment drugsReference 25, Reference 26, Reference 27. Warn all travellers, and especially long-term travellers, expatriates and missionaries, about counterfeit drugs and encourage them to buy a supply of medication in countries where strict quality control measures are in place. If Coartem® (artemether-lumefantrine),, which is not yet licensed for distribution in Canada but is recommended by the World Health Organization as first-line treatment for P. falciparum malaria in Africa, is recommended, travellers should buy it in countries where counterfeiting is unlikely (e.g. in Europe or the USA)Reference 28. Although long-term atovaquone-proguanil prophylaxis may be too expensive for most long-term travellers and expatriates, long-term travellers may choose to purchase enough for one or two self-treatment courses to keep in their medical kitReference 29.

Terminal prophylaxis

Terminal prophylaxis is more of a concern in long-term than in short-term travellers. Expatriates and the military deserve careful consideration (see Chapter 4 “Prevention—Chemoprophylaxis Regimens”).

Table 5.3.1: Evidence-based medicine recommendations
Recommendation EBM Rating

Abbreviation: EBM, evidence-based medicine; RDT, rapid diagnostic test.

Note: For a description of the categories and quality of evidence of the recommendations, see Appendix IV.

Guidelines for the prevention of malaria in long-term travellers or expatriates should not deviate considerably from recommendations for short-term travellersReference 30. B III
Training in the use of RDTs is reasonable for long-term travellersReference 23, Reference 30. C III
Education about counterfeit antimalarial medications is important for long-term travellers who are more likely to buy drugs in countries without quality controlsReference 25, Reference 26, Reference 27. C II
Consider primaquine for terminal prophylaxis (see Chapter 8) for military personnel, long-term travellers or expatriates returned from regions with P. vivaxtransmissionReference 17, Reference 28, Reference 30. A I

References

Reference 1

Frame JD, Lange WR, Frankenfield DL. Mortality trends of American missionaries in Africa, 1945–1985. Am J Trop Med Hyg 1992 Jun;46(6):686–90.

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Reference 2

Toovey S, Moerman F, van GA. Special infectious disease risks of expatriates and long-term travelers in tropical countries. Part I: malaria. J Travel Med 2007 Jan;14(1):42–9.

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Reference 3

Schneider G. Malaria prevention for long-term workers overseas, choice or necessary evil? Dissertation University of London, London School of Hygiene and Tropical Medicine; 1998.

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Reference 4

Adera T, Wolfe MS, Guire-Rugh K, Calhoun N, Marum L. Risk factors for malaria among expatriates living in Kampala, Uganda: the need for adherence to chemoprophylactic regimens. Am J Trop Med Hyg 1995 Mar;52(3):207–12.

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Reference 5

Lobel HO, Varma JK, Miani M, Green M, Todd GD, Grady K, et al. Monitoring for mefloquine-resistant Plasmodium falciparum in Africa: implications for travelers’ health. Am J Trop Med Hyg 1998 Jul;59(1):129–32.

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Reference 6

Onwujekwe O, Kaur H, Dike N, Shu E, Uzochukwu B, Hanson K, et al. Quality of anti-malarial drugs provided by public and private healthcare providers in south-east Nigeria. Malar J 2009;8:22.

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Reference 7

Korhonen C, Peterson K, Bruder C, Jung P. Self-reported adverse events associated with antimalarial chemoprophylaxis in peace corps volunteers. Am J Prev Med 2007 Sep;33(3):194–9.

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Reference 8

Schlagenhauf P, Tschopp A, Johnson R, Nothdurft HD, Beck B, Schwartz E, et al. Tolerability of malaria chemoprophylaxis in non-immune travellers to sub-Saharan Africa: multicentre, randomised, double blind, four arm study. BMJ 2003 Nov 8;327(7423):1078.

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Reference 9

Knobloch J. Long-term malaria prophylaxis for travelers. J Travel Med 2004 Nov;11(6):374–8.

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Reference 10

Schlagenhauf P, Petersen E. Malaria chemoprophylaxis: strategies for risk groups. Clin Microbiol Rev 2008  Jul;21(3):466–72.

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Reference 11

Berg J, Visser LG. Expatriate chemoprophylaxis use and compliance: past, present and future from an occupational health perspective. J Travel Med 2007 Sep;14(5):357–8.

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Reference 12

Hamer DH, Ruffing R, Callahan MV, Lyons SH, Abdullah AS. Knowledge and use of measures to reduce health risks by corporate expatriate employees in western Ghana. J Travel Med 2008 Jul;15(4):237–42.

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Reference 13

Dahlgren AL, Deroo L, Avril J, Bise G, Loutan L. Health risks and risk-taking behaviors among International Committee of the Red Cross (ICRC) expatriates returning from humanitarian missions. J Travel Med 2009 Nov;16(6):382–90.

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Reference 14

Neuberger A, Klement E, Reyes CM, Stamler A. A cohort study of risk factors for malaria among healthcare workers in equatorial Guinea: stay away from the ground floor. J Travel Med 2010 Sep;17(5):339–45.

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Reference 15

Machault V, Orlandi-Pradines E, Michel R, Pages F, Texier G, Pradines B, et al. Remote sensing and malaria risk for military personnel in Africa. J Travel Med 2008 Jul;15(4):216–20.

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Reference 16

Mayet A, Lacassagne D, Juzan N, Chaudier B, Haus-Cheymol R, Berger F, et al. Malaria outbreak among French army troops returning from the Ivory Coast. J Travel Med 2010 Sep;17(5):353–5.

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Reference 17

Kotwal RS, Wenzel RB, Sterling RA, Porter WD, Jordan NN, Petruccelli BP. An outbreak of malaria in US Army Rangers returning from Afghanistan. JAMA 2005 Jan 12;293(2):212–6.

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Lobel HO, Bernard KW, Williams SL, Hightower AW, Patchen LC, Campbell CC. Effectiveness and tolerance of long-term malaria prophylaxis with mefloquine. Need for a better dosing regimen. JAMA 1991 Jan 16;265(3):361–4.

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Lobel HO, Miani M, Eng T, Bernard KW, Hightower AW, Campbell CC. Long-term malaria prophylaxis with weekly mefloquine. Lancet 1993 Apr 3;341(8849):848–51.

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Ohrt C, Richie TL, Widjaja H, Shanks GD, Fitriadi J, Fryauff DJ, et al. Mefloquine compared with doxycycline for the prophylaxis of malaria in Indonesian soldiers. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1997 Jun 15;126(12):963–72.

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Reference 21

Committee to Advise on Tropical Medicine and Travel. Statement on personal protective measures to prevent arthropod bites. Can Commun Dis Rep 2012;38 (ASC-3):1–18.

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Reference 22

Schlagenhauf P, Steffen R, Tschopp A, Van Damme P., Mittelholzer ML, Leuenberger H, et al. Behavioural aspects of travellers in their use of malaria presumptive treatment. Bull World Health Organ  1995;73(2):215–21.

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Funk M, Schlagenhauf P, Tschopp A, Steffen R. MalaQuick versus ParaSight F as a diagnostic aid in travellers’ malaria. Trans R Soc Trop Med Hyg 1999 May;93(3):268–72.

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Roukens AH, Berg J, Barbey A, Visser LG. Performance of self-diagnosis and standby treatment of malaria in international oilfield service employees in the field. Malar J 2008;7:128.

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Dondorp AM, Newton PN, Mayxay M, Van DW, Smithuis FM, Yeung S, et al. Fake antimalarials in Southeast Asia are a major impediment to malaria control: multinational cross-sectional survey on the prevalence of fake antimalarials. Trop Med Int Health 2004 Dec;9(12):1241–6.

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Newton P, Proux S, Green M, Smithuis F, Rozendaal J, Prakongpan S, et al. Fake artesunate in southeast Asia. Lancet 2001 Jun 16;357(9272):1948–50.

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World Health Organization. Guidelines for the treatment of malaria, Second edition. 2010.

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Reference 29

Bryan JP. Cost considerations of malaria chemoprophylaxis including use of primaquine for primary or terminal chemoprophylaxis. Am J Trop Med Hyg 2006 Sep;75(3):416–20.

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Reference 30

Chen LH, Wilson ME, Schlagenhauf P. Prevention of malaria in long-term travelers. JAMA 2006 Nov 8;296(18):2234–44.

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