ARCHIVED - Supplement: Canadian Recommendations for the Prevention and Treatment of Malaria Among International Travellers

4. Prevention - Chemoprophylactic Regimens

Selection of Antimalarial Drugs for Individual Travellers

Malaria causes severe illness, which may be life- threatening. Case-fatality rates associated with P. Falciparum malaria increase to 20% in severe or complicated cases; therefore, it is preferable to prevent the disease rather than treat someone after symptoms develop. Given the variety of choices in medication, a traveller at risk of malaria should be encouraged to use chemoprophylaxis along with personal protective measures against insect bites (37) (see Chapter 3).

Antimalarial drugs have the potential to cause side effects and should be prescribed only after completion of an individual risk assessment (as outlined in Chapter 2) to ensure that only travellers truly at risk of malaria infection receive antimalarial chemoprophylaxis. In deciding between the various chemoprophylactic options, the health care provider must weigh the traveller's underlying health status; other medications being taken; malaria drug effectiveness; risks for and character of adverse drug reactions; as well as the individual's level of risk avoidance for malaria.

Most users of antimalarial chemoprophylaxis will have no or only minor adverse reactions ^{(56, 57, 58, 59, 60, 61)}. However, preconceived ideas about side effects may influence the traveller's confidence in a particular medication option and should be considered in the selection process. If adverse events do occur, they can have a significant impact not only on the traveller's health but also on his or her adherence to the medication regimen. One option available is a trial of medication in advance of travel to assess tolerability. To keep adverse effects to a minimum, it is essential that all travellers be well informed about the dosing schedule, including time of day and association with food, as well as precautions regarding sun exposure or other advice, depen ding on the drug used. While several antimalarial drugs may be equally efficacious when studied in clinical trials, their effectiveness is a measure of protection offered in real life. The more knowledgeable and compliant the patient, the closer the effectiveness will be to the efficacy of a given chemoprophylactic agent.

Fatal malaria has occurred in travellers who have discontinued an effective antimalarial drug in favour of one that is less protective ^{(6,8, 62, 63)}. Therefore, travellers who are tolerating their chemoprophylactic regimen should be advised to continue it regardless of what they are told by other travellers. Medications used in other areas of the world may be less effective or associated with serious adverse effects and are not recommended. Examples include proguanil alone (Paludrine^®), pyrimethamine (Daraprim^®), dapsone/pyrimetha-mine (Maloprim^®) and mefloquine/sulfadoxine-pyrimethamine (Fansimef^®).

Selection of Antimalarial Drugs for Specific Regions

Medication should be considered to reduce the risk of travellers acquiring clinical malaria during evening, overnight and/or early morning exposure in the following areas:

Urban and rural areas

Higher risk: sub-Saharan Africa (except most of South Africa) and Oceania (including Papua New Guinea, Papua [Irian Jaya], Solomon Islands and Vanuatu).

Low to moderate risk: Haiti, India, Bangladesh, Pakistan, Nepal (Terai region), Bhutan and the Middle East.

Rural areas

Low risk: Southeast Asia; Central and South America; and certain parts of Mexico, North Africa and the Dominican Republic.

Travellers should be informed that antimalarial medication can markedly decrease the risk of acquiring symptomatic malaria ^{(56, 57, 58, 59, 60, 61, 64)}, but none of these agents can guarantee complete protection. Personal protective measures complement chemoprophylactic drugs ⁽³⁷⁾. Symptoms due to malaria may occur as early as 1 week after first exposure and as late as several years after travellers leave a malarial region, whether or not chemoprophylaxis has been used. Most travellers who acquire P. Falciparum infection will experience symptoms within 2 months of exposure ⁽⁶⁵⁾. Falciparum malaria can be effectively treated early in its course, but delay in therapy may result in a serious and even fatal outcome.

Fever occurring in a traveller within 3 months of departure from a malaria- endemic area is a medical emergency and should be investigated urgently by means of thick and thin blood films. If symptoms persist, these films should be repeated at 12- to 24-hour intervals at least twice if the patient remains symptomatic.

Although minor differences in expert opinion exist between various jurisdictions (i.e., United States, Europe, Canada), there is universal acceptance that malaria chemoprophylaxis is an essential component of malaria prevention. During travel, many individuals will encounter other travellers or health care providers who will counsel them to change or stop their antimalarial medication (especially mefloquine), leaving them without an acceptable alternative chemoprophylactic and at high risk of acquiring potentially life-threatening malaria. Travellers should be warned of this possibility; as well, the antimalarial guidelines and the risks and benefits of effective chemoprophylaxis should be reinforced. Appendix III, Frequently Asked Questions About Malaria, may aid the practitioner in answering travellers' questions. If desired, this text can be copied and provided to the traveller.

Table 1 summarizes the different chemoprophylactic options according to the presence of drug resistance. Chapter 8 provides details regarding individual chemoprophylactic agents.

Table 1: Malaria chemoprophylaxis regimens for at-risk individualsa according to presence of drug resistance

Chloroquine-sensitive regions

Chloroquine-sensitive regions are malarial areas where chloroquine resistance has not been documented or is not widely present. These include Haiti, the Dominican Republic, Central America west of the Panama Canal, North Africa, parts of the Middle East, and west/central China. See individual countries in Appendix I for more specific recommendations.

Drugs of choice: Chloroquine (Aralen^®) is the drug of choice for travellers to areas with chloroquine-sensitive malaria. Hydroxychloroquine (Plaquenil^®) is an acceptable equivalent alternative ⁽⁶²⁾. Chloroquine or hydroxychloroquine is taken once weekly, beginning 1 week before entering a chloroquine-sensitive malarial region, during the period of exposure, and for 4 weeks after leaving the malarial region.

Alternatives: For individuals unable to tolerate chloroquine or hydroxychloroquine, atovaquone/ proguanil, doxycycline or mefloquine should be used (see next section and Chapter 8).

Chloroquine-resistant regions

The chloroquine-resistant regions refer to most of sub-Saharan Africa, South America, Oceania and Asia. See individual countries in Appendix I for specific recommendations. Note that some border areas of Thailand, Myanmar (Burma), Laos and Cambodia, as well as southern Vietnam, are also mefloquineresistant regions ^{(20, 66, 67)} (see next section).

There are sufficient data in semi-immune and non- immune hosts in various geographic locations to conclude that atovaquone/proguanil, doxycycline and mefloquine are equally efficacious in the prevention of chloroquine-resistant malaria ^{(56, 57, 58, 59, 60, 61)}.

Drugs of choice: Atovaquone/proguanil, doxycycline or mefloquine ^{(56, 57, 58, 59, 60, 61, 64)} (see Table 1 and Chapter 8 for details on each medication).

Atovaquone/proguanil is taken daily, beginning 1 day before entering the malarial region, during the period of exposure, and for 1 week after leaving the malarial region ⁽⁶⁸⁾.

Doxycycline is taken daily, beginning 1 day before entering the malarial region, during the period of exposure, and for 4 weeks after leaving the malarial region ⁽⁵⁷⁾.

Mefloquine is taken weekly, beginning 1 week before entering the malarial region (or 3 weeks before, to assess tolerability), during the period of exposure, and for 4 weeks after leaving the malarial region ⁽⁵⁷⁾.

Alternatives: Although atovaquone/proguanil, doxycycline and mefloquine are well tolerated prophylactic antimalarial drugs ⁽⁶⁹⁾, for individuals unable to tolerate these drugs primaquine is an acceptable alternative ⁽⁵⁸⁾. Primaquine is taken daily, beginning 1 day before entry into the malarial region, during the period of exposure, and for 7 days after leaving the malarial region.

NOTE: Primaquine is CONTRAINDICATED in G6PD (glucose-6-phosphate dehydrogenase) deficiency and CONTRAINDICATED in pregnancy (see Chapters 5 and 8 for details on medication).

Chloroquine- and mefloquine-resistant regions

Resistance to both chloroquine and mefloquine has been reported sporadically from various countries in Asia, Africa and in the Amazon basin. However, it has not been found to be a significant problem except in rural, wooded regions where Thailand borders with Myanmar (Burma), Cambodia ^{(66, 67)} and Laos, as well as in southern Vietnam ^{(20, 70)}. While these areas are infrequently visited by tourists, use of personal protective measures should be optimized for those travelling there ⁽³⁷⁾.

Drugs of choice: Doxycycline or atovaquone/ proguanil (see Table 1 and Chapter 8). Doxycycline is taken daily, beginning 1 day before entering the malarial region, during the period of exposure, and for 4 weeks after leaving the malarial region.

Alternatives: There are no trials of alternative prophylactic agents for travellers to these areas; therefore, unnecessary travel, especially by pregnant women and preschool children, should be avoided. Atovaquone/proguanil (Malarone) has been a successful treatment for multidrug-resistant malaria in Thailand (71), and this medication may be considered for travellers at risk in whom doxycycline is contraindicated or not tolerated. Atovaquone/ proguanil is taken daily, beginning 1 day before entering the malarial region, during the period of exposure, and for 1 week after leaving the malarial region.

Primaquine Terminal Prophylaxis for Prevention of Relapses of P. vivax and P. ovale

P. vivax and P. ovale parasites can persist in the liver and cause relapses for as long as 5 years after routine chemoprophylaxis has been discontinued ^{( 65, 72)}. Although considered less virulent than Falciparum malaria, P. vivaxstill carries the potential for significant morbidity requiring intensive care ⁽⁷³⁾. Since most malarial areas of the world (except Haiti and the Dominican Republic) have at least one species causing relapsing malaria, travellers to these areas have some risk of acquiring either P. vivax or P. ovale. Primaquine decreases the risk of relapses by acting against the persistent liver stages (hypnozoites) of P. vivax and P. ovale. Primaquine terminal prophylaxis is administered after the traveller has left a malaria-endemic area, usually during or after the post-travel period of chemoprophylaxis. The data pertaining to the risk of relapse are limited. A total of 38 (5.2%) of a 725 US Army Ranger task force of soldiers in Afghanistan were found to have P. vivaxmalaria after leaving Afghanistan, yielding an attack rate of 52.4 cases per 1,000 soldiers. Diagnosis was confirmed at a median of 233 days after return from the malaria-endemic region ⁽⁷³⁾. Military personnel, long-term travellers and expatriates are groups that warrant consideration for terminal prophylaxis if they have resided in regions with high P. vivaxendemicity. Any traveller who returns to Canada with a history of a P. vivaxor P. ovale diagnosis while abroad should also be considered for terminal prophylaxis ⁽⁷⁴⁾. Primaquine is contraindicated in pregnant women and individuals deficient in G6PD (see Chapter 8 for contraindications and precautions).

Differences in Approaches to Malaria Chemoprophylaxis in Other Jurisdictions

There are more similarities than significant differences between the major expert groups. CATMAT consults all major sources of malaria prevention information, including the WHO ⁽⁷⁵⁾, the US CDC ⁽²⁰⁾ and the UK Health Protection Agency Advisory Committee on Malaria Prevention (ACMP) ⁽⁷⁶⁾. In keeping with the guidelines, CATMAT recommends chloroquine for the prevention of malaria in chloroquine-sensitive regions and atovaquone-proguanil, doxycycline or mefloquine as three equivalent options for the prevention of malaria in chloroquine-resistant regions. The detailed recommendations regarding when to start and stop malaria chemoprophylaxis are also consistent among major guidelines, and they provide the option of emergency standby therapy for travellers who are going to remote areas where they may be unable to access medical assistance within 24 hours.

The differences in guidelines come in some of the details. While guidelines provide detailed country- specific information on malaria risk and malaria chemoprophylaxis recommendations, some recommended regimens may differ from CATMAT guidelines, particularly in countries where malaria risk is lower and chemoprophylactic decisions need to consider drug intolerances as well. For the most part, CATMAT guidelines are consistent with the CDC's Yellow Book: Health Information for International Travel ⁽²⁰⁾.

CATMAT guidelines are different from the WHO and ACMP guidelines with respect to drug availability and differences in interpretation of available evidence. In chloroquine-sensitive regions, ACMP recommends proguanil as an alternative to chloroquine; however, proguanil alone is not available in Canada, and CATMAT, CDC and WHO do not recommend its use alone. In areas of low to moderate levels of malaria transmission combined with low to moderate levels of chloroquineresistance (e.g., parts of South Asia, Southeast Asia, sub-Saharan Africa and South America), WHO and ACMP recommend a combination of chloroquine and proguanil as a first-line chemoprophylaxis. As chloroquine/proguanil chemoprophylaxis has inferior efficacy compared with atovaquone/ proguanil, doxycycline or mefloquine (77, 78), CATMAT generally does not recommend this regimen.

Emergency standby therapy for short-term travellers is an option recommended by all guidelines, although CATMAT and CDC have more restrictive criteria as to when it should be used. CDC guidelines only recommend atovaquone/proguanil for this use, whereas WHO, ACMP and CATMAT provide more options for emergency standby therapy. However, CATMAT does not recommend the use of mefloquine for therapy under any circumstances because of the high likelihood of severe adverse reactions when using higher therapeutic doses. While CATMAT recommends standby self-treatment, particularly for travellers taking suboptimal malaria chemoprophylaxis, it is only to be used in the event of suspected malaria in travellers who are unable to access medical assistance within 24 hours. For more information about self-treatment, see Chapter 7.

Coadministration of Antimalarial Drugs with Vaccines

Travellers requiring antimalarial medications may also require vaccination against agents for which live, oral, bacterial vaccines exist. Because such vaccines require bacterial replication to induce a protective immune response, simultaneous administration of antibiotics may interfere with vaccine effectiveness. Doxycycline is an antibiotic and should never be coadministered with any live attenuated oral vaccines. Mefloquine and chloroquine have in vitro inhibitory activity against an oral typhoid vaccine ⁽⁷⁹⁾. Proguanil has some antibacterial activity, but coadministration of atovaquone/proguanil with live oral typhoid and cholera vaccines to children has demonstrated no decrease in typhoid and cholera antibody response to the vaccine ⁽⁸⁰⁾. However, coadministration of proguanil and chloroquine with live oral typhoid and cholera vaccines decreased vaccine immunogenicity ^{( 81)}. Vaccine efficacy studies measuring the impact on clinical typhoid and cholera of the coadministration of antimalarials with live oral typhoid and cholera vaccines have not yet been performed in children or adults. For chloroquine, mefloquine, atovaquone/proguanil or primaquine, live attenuated oral vaccines should be taken at least 8 hours after taking these antimalarials ^{(79, 81)}. Formalin- and/or heat-inactivated oral vaccines (such as Dukoral^™) do not contain live bacteria and may be coadministered with antimalarials.

Concurrent use of chloroquine also interferes with the antibody response to intradermal administration of human diploid cell rabies vaccine ⁽⁸²⁾. If this vaccine is administered to someone taking chloroquine, it is recommended that post-vaccine rabies antibodies be used to verify an adequate immunologic response.