3 7 4

Long-term malaria prophylaxis is hampered by a lackof standardization and compliance. Advice should beindividually optimized to achieve a high degree of pro-tection and compliance. Individual risk assessment takesinto consideration the duration of stay in the endemicarea, the individual exposure, the seasonal transmissionrates, and the drug-resistance situation.Methods for pre-vention of exposure may help reduce the reliance onchemoprophylactic drugs.Exposure-prevention methodsmay be combined with standby treatment in lower trans-mission areas if the traveler has been trained to take theantimalarials appropriately. Although suitable for long-term use, chloroquine and chloroquine-proguanil can-not be used as prophylaxis owing to high resistance ratesin most endemic regions. Mefloquine is suitable formost malaria-endemic regions,although its use is restrictedby neuropsychiatric side effects, particularly in women.Doxycycline is also appropriate; experience with long-term malaria prophylaxis is available for up to 6 months.The use of atovaquone-proguanil is restricted to 28 daysin some countries,but clinical studies indicate that its useis suitable for at least 20 weeks.Primaquine is also effec-tive for chemoprophylaxis; experience is limited to 1 yearof protection against falciparum and vivax malaria.Whengiving individual recommendations to a traveler, specialconsiderations for backpackers, expatriates, and frequenttravelers may apply.

Principal Considerations

Travel, for business or pleasure, in malaria-endemicregions often lasts for up to only 4 weeks’ duration.

Those who travel for longer than 4 weeks are consid-ered long-term travelers, such as backpackers, expatriateswho more or less live in one place for months or years,and business travelers who frequently visit tropical areas.In the United Kingdom, long-term travelers are definedas those who are visiting or traveling through malaria-endemic countries for > 6 months.1

There is a negative correlation between complianceof prophylactic measurements and the duration of stayin the endemic area. Long-term travelers tend to adopta nonchalant attitude toward malaria, as is observed inthe local population,and therefore often disregard the rec-ommendations of their physicians back home.

In general, the degree of compliance varies widely.It is by and large accepted that it is more appropriate toindividualize rather than to standardize malaria prophyl-axis recommendations for long-term travelers; however,expert recommendations are often vague. The GermanSociety of Tropical Medicine, for instance, does not giveany specific recommendation but stresses the need for expe-rienced tropical doctors to give appropriate individualadvice.2 Publications from the Centers for Disease Con-trol and Prevention (CDC) do not provide any specific rec-ommendation for long-term travelers.3 The World HealthOrganization (WHO) recommendations on drugs appro-priate for long-term application are brief.4 Recently, theHealth Protection Agency Advisory Committee onMalaria Prevention for UK Travellers has provided a sup-plement to the guidelines for malaria prevention in trav-elers from the United Kingdom for 2003 titled “MalariaProphylaxis for Long-Term Travellers.”1 This documentcontains a more complete description of antimalarials andadditional preventive measures, together with recom-mendations for malaria chemoprophylaxis for individualcountries, the latter of which are similar to the Germanguidelines, which also provide country-, region-, andseason-specific recommendations for antimalarial drugs.2

Pretravel advice should provide information onindividual risk assessment. It is essential to clarify that tem-porarily exposed travelers are at greater risk than theendemic population since they lack both genetic pro-tective factors and immunity. Moreover, the statisticalprobability of being infected by sporozoites increases tonearly 100% when, for example, the stay in the endemicarea exceeds 4 weeks and 10 bites per night are received,assuming that 1% of the bites are infective.5

Long-Term Malaria Prophylaxis for TravelersJürgen Knobloch

Jürgen Knobloch, ProfDrMed: Institute of Tropical Medicine,University of Tübingen, Tübingen, Germany.

The author has no financial or other conflicts of interest todisclose.

This article was presented at the 8th Conference of theInternational Society of Travel Medicine (CISTM8), in NewYork, New York, USA, on May 11, 2003.

Reprint requests: Jürgen Knobloch, Institute of TropicalMedicine, Keplerstr. 15, D-72074 Tübingen, Germany.

J Travel Med 2004; 11:374–378.

An important factor for risk assessment is the drug-resistance situation in the travel area. Drugs that areknown to be poorly effective should not be used sincea grade 1 or 2 resistance breakthrough might further ham-per a differential diagnosis when atypical clinical malariaoccurs. This has been shown to be particularly true fortravelers developing subclinical forms of falciparummalaria under chloroquine-proguanil prophylaxis.6 Thisdrug combination has been shown to have an average pro-tective efficacy of < 70%, and it is therefore no longerconsidered adequate for most malaria-endemic areas.7

The Tools

Methods for prevention of exposure,believed to be ini-tiated by armies of the classical era and later by Teutonictribes, consist of avoiding swamps and staying in higher-altitude camps.8 Today’s recommendations include theuse of window screens,pyrethroid-impregnated bed nets,repellents (on skin, soap,and clothes), and mosquito coils.Conventional formulas of repellents, such as diethyltolu-amide,are more effective than plant products such as soy-bean oil or citronella.9 Wearing long-sleeved shirts,pants,and socks to cover the skin is usually not acceptable to long-term travelers.Travelers should be encouraged to spray theirresidences with long-lasting insecticides and to destroy pos-sible mosquito breeding grounds. When explained care-fully, these methods are generally well accepted,and whenappropriately applied, they are extremely helpful in pre-venting a reliance on prophylactic drugs.

It is more difficult to give standardized recommen-dations for chemoprophylaxis. Moreover, the compliancewith malaria chemoprophylaxis is extremely poor, par-ticularly in long-term, occupational travelers and back-packers.The main reasons for this reluctance seem to befear of long-term side effects and conflicting advice onprophylaxis.10,11 One option is to convince the travelerto take prophylactic drugs at least temporarily when thelocal transmission rate increases seasonally. For the restof the year, standby treatment may be sufficient.Unfortu-nately,medical facilities capable of producing a qualifieddiagnosis are not common in hyper- and holoendemicmalaria areas, where the patients sometimes seem moreexperienced than their physicians.12 Thus, the appropriateapplication of standby treatment is currently more or lessunverifiable in long-term travelers. In any case, travelersshould be encouraged to use good manufacturing prac-tice (GMP) drugs from home since the rate of counter-feit drugs is high in some developing countries.

Long-term malaria chemoprophylaxis is generallybelieved to have been implemented for the first time in1854, when Dr. William Balfour Baikie effectively puthis staff on quinine while exploring the Niger River inWest Africa.8 Reports of the US Sanitary Commission,

however,provide evidence that quinine was added as earlyas 1840 to the whiskey of the military post staff at TampaBay,Florida, successfully preventing “miasmatic disease”or “African fever.”13

Today the indications for various short-term pro-phylaxis measurements are well established,whereas the useof long-term chemoprophylaxis is still open for extensivemodification.During recent decades the majority of malariadrugs have been tested for long-term use. Some of thesedrugs are no longer considered useful for travelers, such assulfadoxine-pyrimethamine,14–16 mefloquine-sulfadoxine-pyrimethamine,17 and dapsone-pyrimethamine.18

Drugs for Long-Term Use

WHO recommendations for chloroquine are gen-erally accepted among physicians as the standard.The drugis appropriate for long-term use, and the risk of seriousside effects associated with long-term prophylactic useis low.3 Retinopathy associated with long-term use ofchloroquine is a rare event, even if a cumulative chloro-quine dose in excess of 300 g is used,19 although it hasbeen known to occur at lower doses.20 Therefore,chloro-quine requires screening for retinal changes once every2 years when taken for more than 3 (700 mg/wk) or 5(300 mg/wk) years. With increasing drug resistance,however, indications for such chemoprophylaxis aredecreasing. In Germany, for example, chemoprophylaxisis no longer recommended for travelers going to anyendemic area, with or without proguanil (which is usu-ally combined with chloroquine).Using daily proguanilin addition to chloroquine has not always been shownto provide additional protection.21

Because of increasing drug resistance in the past 15years, chloroquine and proguanil have been graduallyreplaced by mefloquine for both short- and long-termprophylaxis.22 Major studies of mefloquine tolerability,as well as worldwide monitoring, have shown that seri-ous adverse events are rare,23 and it is usually safe and welltolerated for long-term prophylaxis, particularly inmales.3,22,24,25 There is no measurable accumulation ofmefloquine in the serum,15,16,26 even when every-other-week dosing is replaced by weekly dosing, the latterwhich is more effective as shown in the 1990s.25,27 Meflo-quine-resistant parasites, however, have been isolatedfrom military, long-term travelers since the early 1990s.25

Female travelers should be informed of an increasedrisk of neuropsychiatric side effects during long-term pro-phylaxis.Mefloquine plasma levels do not show substantialgender-specific differences28; thus, recommendations ondose reduction for female travelers under long-termmefloquine prophylaxis so far lack scientific support.

Both mefloquine and doxycycline are appropriateprophylactic drugs for chloroquine-resistant infections,

Knobloch, Long-Term Malar ia Prophylax is for Trave ler s 375

3 7 6 Journal of Trave l Medic ine , Volume 11, Number 6

which now occur in nearly all of the Plasmodium falci-parum–endemic areas.There is little information regard-ing long-term (> 6 mo) use of doxycycline; however,available data are reassuring.29 There is considerableinformation regarding its use in long-term therapy foracne, Q fever endocarditis,30 and small, asymptomatic,abdominal aortic aneurysms.31 As for malaria chemo-prophylaxis, the drug has predominantly been tested bymilitary personnel, and the incidence of adverse eventsas well as the effectiveness were acceptable.29,32 Themajor side effects are episodes of cutaneous photosen-sitivity reactions, tooth discoloration, yeast infection,and gastrointestinal symptoms,31 including esophageal per-foration.National regulations, such as those regarding thepatient’s formal or informal consent, should be consid-ered when the drug is not specifically licensed for malariaprophylaxis.There is no general limitation or restrictionfor the use of doxycycline in the CDC recommenda-tions.2 The monohydrate formula of doxycycline is bet-ter tolerated than the hyclate formula.33

In some countries (not the United States), the useof atovaquone-proguanil is restricted to 28 days plus 1 to2 days before and 1 week after the stay in the endemicarea. However, in single observations as well as in clini-cal studies, the drug has proved to be appropriate for long-term prophylaxis. For example, in Indonesia over a20-week duration, the daily dose of 250 mg atovaquoneplus 100 mg proguanil (1 adult tablet of Malarone) pre-vented most of the 148 transmigrants from contractingvivax or falciparum malaria with a protective efficacy of84 and 96%,respectively.34 A 6-month safety study in Dan-ish soldiers showed that the drug was well tolerated andeffective.35 A recent postmarketing surveillance showedatovaquone-proguanil to be well tolerated by long-termtravelers taking the drug for up to 34 weeks.36 Since thedrug is considered causal prophylaxis, that is, acting on theplasmodial liver stage, it may be discontinued after 1week,as compared with 4 weeks after departure from themalarious area in the case of mefloquine. It is particularlyuseful for a subset of long-term travelers, namely, thosewho travel frequently to and from endemic areas, to pro-vide them some relief from continuous drug consump-tion.Atovaquone-proguanil has been well accepted by thetravel community because of its lower rate of severe andneuropsychiatric side effects compared with mefloquine.37

Primaquine is used for relapse prevention againstvivax and ovale malaria.It is also effective for causal chemo-prophylaxis.In order not to risk severe hemolysis,those withglucose-6-phosphate dehydrogenase deficiency should beexcluded.Recently,Javanese transmigrants were protectedagainst falciparum and vivax malaria at an efficacy of 93%when they took daily doses of 30 mg for 20 weeks.38 Anearlier study in Javanese men showed primaquine to be

94.5% effective for prevention of Plasmodium falciparuminfection and 90.4% for Plasmodium vivax infection whenused for 1 year.39 In both studies the drug was well toler-ated. Primaquine is usually not licensed for long-termmalaria chemoprophylaxis.The CDC recently added it totheir list of approved drugs but did not stipulate whetherit should be used for short or long terms.2

In clinical phase 2 studies,another 8-aminoquinoline,tafenoquine ,has been shown to be effective in 86 or 89%when given in 200 or 400 mg weekly doses, respectively,for up to 13 weeks in Kenya.40 Apparently, the drug willnot be released for marketing in the near future.

Special Considerations for Backpackers

Backpackers and other travelers who move from onemalarious area to another are not usually familiar withlocal medical facilities, and they are unable to estimatethe laboratory quality of malaria testing. Continuouschemoprophylaxis should therefore be encouraged whenindicated.Priority should be given to drugs that may beused for both chemoprophylaxis and standby, such asmefloquine and atovaquone-proguanil.

Special Considerations for Expatriates

Expatriates who live where malaria is hyper- orholoendemic should be encouraged to take continuouschemoprophylaxis during the high-transmission periodsand to be on standby for the rest of the season. Theyshould rely on local malaria testing and treatment onlyif there is external quality control of test results.

Special Considerations for Frequent Travelers

Travelers who frequently visit malaria-endemic areasshould use chemoprophylaxis, standby, or exposure pro-phylaxis as indicated. If the journey is < 1 week (mini-mum incubation period of falciparum malaria),continuousmalaria chemoprophylaxis is usually not necessary if thetraveler returns to a country with high medical standardswith regard to diagnosis and treatment of malaria. Someexperts, however, always recommend chemoprophylaxisfor highly endemic areas regardless of the journey period.If chemoprophylaxis is indicated,priority should be givento drugs that require the minimum period of applicationsuch as atovaquone-proguanil rather than mefloquine.

Conclusions

In individual cases of long-term travel to malaria-endemic regions, it may be difficult to compromisebetween our more or less evidence-based medical

Knobloch, Long-Term Malar ia Prophylax is for Trave ler s 377

recommendation and the compliance to be expectedfrom the traveler. When accompanied with appropriateinformation on the respective malaria situation,more gen-eral prophylaxis methods are easily accepted, whereas thelong-term use of drugs is not. Thus, even for high-trans-mission areas, it may be indicated to recommendchemoprophylaxis at intervals,for example,in periods of highmalaria transmission during the rainy season or during tripsfrom low- to high-transmission areas.1 In summary, thefollowing issues should be considered for long-term trav-elers to hyper- and holoendemic malaria regions:

• Give appropriate information on the respectivemalaria situation.

• Encourage exposure prophylaxis including sprayingof the residence and control of mosquito breedinggrounds.

• Give information on the drugs appropriate for theindividual case.

• Encourage chemoprophylaxis for periods of hightransmission.

• Encourage standby treatment for periods withoutchemoprophylaxis.

• Make sure that GMP drugs are used for chemo-prophylaxis and standby treatment.

• Take caution in recommending local clinics formalaria testing if there is no information on the qual-ity standard.

References

1. Hughes C, Tucker R, Bannister B, et al. Malaria prophylaxisfor long-term travellers. Commun Dis Public Health 2003;6:200–208.

2. German Society of Tropical Medicine. Empfehlungen zurMalariaprophylaxe. Personen mit längeren oder häufigwiederholten Tropenaufenthalten. 2003. Available at:http://www.dtg.mwn.de/malaria/langzeit.htm (accessedApril 28, 2004).

3. Centers for Disease Control and Prevention.Travelers’health.2003. Available at: http://www.cdc.gov/travel/malariadrugs2.htm (accessed April 28, 2004).

4. World Health Organization. International travel and health.Geneva: World Health Organization, 2003.

5. Zucker JR, Carnevale PJ. Malaria. Epidemiology and pre-vention of exposure. In: Du Pont HL, Steffen R, eds. Text-book of travel medicine and health. Hamilton: BC Decker,1997:101–108.

6. Klement E, Chauveheid MP, Thellier M, et al. Subacuteclinical forms of Plasmodium falciparum malaria in travelersreceiving chloroquine-proguanil prophylaxis.Clin Infect Dis2001; 33:1614–1615.

7. Hogh B, Clarke PD, Camus D, et al for the Malarone Inter-national Study Team. Atovaquone-proguanil versus chloroquine-proguanil for malaria prophylaxis in non-immune

travellers: a randomised, double-blind study. Lancet 2000;356:1888–1894.

8. Knobloch J,ed.Malaria.Grundlagen und klinische Praxis.Bre-men: UNI-MED Verlag, 2003.

9. Fradin MS, Day JF. Comparative efficacy of insect repellentsagainst mosquito bites. N Engl J Med 2002; 347:13–18.

10. Fegan D,Glennon J.Malaria prophylaxis in long-term expa-triate mineworkers in Ghana.Occup Med 1993;43:135–138.

11. Chatterjee S. Compliance of malaria chemoprophylaxisamong travelers to India. J Travel Med 1999; 6:7–11.

12. Philipps J, Radloff PD, Lehman LG, et al. Clinical diagnosisof malaria:can the patients help us improve? Trans R Soc TropMed Hyg 1996; 90:42 .

13. United States Sanitary Commission.Report of a committeeappointed by resolution of the sanitary commission, to pre-pare a paper on the use of quinine as a prophylactic againstmalarious diseases. New York: WMC Bryant & Co., 1861.

14. Stemberger H,Leimer R,Wiedermann G.Tolerability of long-term prophylaxis with Fansidar: a randomized double-blindstudy in Nigeria. Acta Trop 1984; 41:391–399.

15. Hellgren U, Angel VH, Bergqvist Y, et al. Plasma concen-trations of sulfadoxine-pyrimethamine and of mefloquine dur-ing regular long-term malaria prophylaxis.Trans R Soc TropMed Hyg 1990; 84:46–49.

16. Rombo L, Angel VH, Friman G, et al. Comparative tolera-bility and kinetics during long-term intake of Lariam and Fan-sidar for malaria prophylaxis in nonimmune volunteers.TropMed Parasitol 1993; 44:254–256.

17. Kollaritsch H, Stemberger H, Mailer H, et al. Tolerability oflong-term malaria prophylaxis with the combination meflo-quine + sulfadoxine + pyrimethamine (Fansimef): results ofa double-blind field trial versus chloroquine in Nigeria.Trans R Soc Trop Med Hyg 1988; 82:524–529.

18. Cook IF, Kish MY. Haematological safety of long-termmalarial prophylaxis with dapsone-pyrimethamine.Med J Aust1985; 143:139–141.

19. Lange WR, Frankenfield DL, Moriartry-Sheehan M, et al.No evidence for chloroquine-associated retinopathy amongmissionaries on long-term malaria chemoprophylaxis. Am JTrop Med Hyg 1994; 51:389–392.

20. Bertagnolio S, Tacconelli E, Camilli G, Tumbarello M. Casereport: retinopathy after malaria prophylaxis with chloroquine.Am J Trop Med Hyg 2001; 65:637–638.

21. Lobel HO,Bernard KW,Williams SL, et al.Effectiveness andtolerance of long-term malaria prophylaxis with mefloquine.Need for a better dosing regimen. JAMA 1991;265:361–364.

22. Peragallo MS,Sabatinelli G,Sarnicola G.Compliance and tol-erability of mefloquine and chloroquine plus proguanil forlong-term malaria chemoprophylaxis in groups at particularrisk (the military). Trans R Soc Trop Med Hyg 1999;93:73–77.

23. Schlagenhauf P. Mefloquine for malaria chemoprophylaxis1992–1998: a review. J Travel Med 1999; 6:122–133.

24. Lobel HO, Miani M, Eng T, Bernard KW, et al. Long-termmalaria prophylaxis with weekly mefloquine. Lancet 1993;341:848–851.

25. Hopperus Buma APCC, van Thiel PPAM, Lobel HO, et al.Long-term malaria chemoprophylaxis with mefloquine

3 7 8 Journal of Trave l Medic ine , Volume 11, Number 6

in Dutch mar ines in Cambodia. J Infect Dis 1996;173:1506–1509.

26. Jaspers CAJJ, Hopperus Buma APCC, van Thiel PPAM, etal.Tolerance of mefloquine chemoprophylaxis in Dutch mil-itary personnel. Am J Trop Med Hyg 1996; 55:230–234.

27. Pennie RA, Koren G, Crevoisier C. Steady state pharma-cokonetics of mefloquine in long-term travellers.Trans R SocTrop Med Hyg 1993; 87:459–462.

28. Schwartz E,Potasman I,Rotenberg M,et al. Serious adverseevents of mefloquine in relation to blood levels and gender.Am J Trop Med Hyg 2001; 65:189–192.

29. Shanks GD, Roessler F, Edstein MD, et al. Doxycycline formalaria prophylaxis in Australian soldiers deployed to UnitedNations missions in Somalia and Cambodia.Mil Med 1995;160:443–445.

30. Raoult D, Houpikian P, Tissot Dupont H, et al. Treatmentof Q fever endocarditis: comparison of 2 regimens contain-ing doxycycline and ofloxacin or hydroxychloroquine.ArchIntern Med 1999; 159:167–173.

31. Baxter BT, Pearce WH, Waltke EA, et al. Prolonged admin-istration of doxycycline in patients with small asymptomaticabdominal aortic aneurysms: report of a prospective (PhaseII) multicenter study. J Vasc Surg 2002; 36:1–12.

32. Watanasook C, Singharaj P, Suriyamongkol V, et al. Malariaprophylaxis with doxycycline in soldiers deployed to Thai-Kampuchean border. Southeast Asian J Trop Med PublicHealth 1989; 20:61–64.

33. Pages F, Boutin JP, Meynard JB, et al. Tolerability of doxy-cycline monohydrate salt vs. chloroquine proguanil in

malaria chemoprophylaxis. Trop Med Int Health 2002;7:919–924.

34. Ling J, Baird JK, Fryauff DJ, et al. Randomized, placebo-controlled trial of atovaquone/proguanil for the preventionof Plasmodium falciparum or Plasmodium vivax malaria amongmigrants to Papua, Indonesia. Clin Infect Dis 2002;35:825–833.

35. Petersen E. The safety of atovaquone/proguanil in long-term malaria prophylaxis of nonimmune adults. J Travel Med2003; 10(Suppl 1):S13–S15.

36. Overbosch D. Post-marketing surveillance: adverse eventsduring long-term use of atovaquone/proguanil for travelersto malaria-endemic countries. J Travel Med 2003; 10(Suppl1):S16–S20.

37. Overbosch D, Schilthuis H, Bienzle U, et al. Atovaquone-proguanil versus mefloquine for malaria prophylaxis in non-immune travelers: results from a randomized, double-blindstudy. Clin Infect Dis 2001; 33:1015–1021.

38. Baird JK, Lacy MD, Basri H, et al. Randomized, parallelplacebo-controlled trial of primaquine for malaria prophy-laxis in Papua, Indonesia.Clin Infect Dis 2001;33:1990–1997.

39. Fryauff DJ, Baird JK, Basri H, et al. Randomised placebo-controlled trial of primaquine for prophylaxis of falciparumand vivax malaria. Lancet 1995; 346:1190–1193.

40. Shanks GD, Oloo AJ, Aleman GM, et al. A new primaquineanalogue, tafenoquine (WR 238605), for prophylaxis againstPlasmodium falciparum malaria. Clin Infect Dis 2001;33:1968–1974.