Chapter 4 – Prevention-Chemoprophylaxis regimen: Canadian recommendations for the prevention and treatment of malaria

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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 4: Prevention— chemoprophylaxis regimens

Malaria is a severe life-threatening illness. Even with modern, effective treatments and intensive care support, the case-fatality rate for severe infections of Plasmodium falciparum can be as high as 20%. Thus, prevention of disease is the mainstay of reducing its impact on travellers. A variety of interventions exists to reduce this threat. Chief among these is the use of malaria chemoprophylaxis (see Chapters 5 and 8) along with personal protective measures (PPM) against insect bites^{Reference 1} (see Chapter 3).

Anti-malaral drugs

Most people who take antimalarial chemoprophylaxis will have no or only minor adverse reactions^{Reference 2}, ^{Reference 3}, ^{Reference 4}, ^{Reference 5}, ^{Reference 6}, ^{Reference 7}, ^{Reference 8}. Nevertheless, antimalarial drugs should be prescribed only after completion of an individual risk assessment (see Chapter 2) that takes into consideration the risks and benefits of chemoprophylaxis. In deciding between the various options, the health care provider should consider: the traveller's health status; other medications being taken; malaria drug effectiveness; risks for and character of adverse drug reactions; and the traveller's preferences and risk tolerances.

If adverse events do occur, they can have a significant impact on the traveller's health and on adherence to the medication regimen. One way to test for tolerability is to have a trial of the medication before travelling. To keep adverse effects to a minimum, it is essential that all travellers understand the dosing schedule, including time of day, and whether the chemoprophylaxis should be taken with food, as well as precautions regarding drug-specific side effects (e.g. sun exposure with doxycycline).

The efficacy reported for different antimalarial clinical trials assumes strict adherence to the dosing schedule as well as the use of PPM, such as insect avoidance and use of insect repellents. Some regimens (e.g. mefloquine) are more forgiving of missed doses while some need to be taken on a very regular schedule (e.g. doxycycline) to ensure maximal protection. If travellers are educated on all aspects of malaria prevention and the specific issues around their prophylactic regimen will, they may be more compliant with the treatment schedule.

Selection of antimalarial drugs

Selecting the most appropriate antimalarial chemoprophylaxis involves the health care provider following five steps:

1. Evaluate the traveller's exact travel itinerary to determine their malaria risk profile. Ask specific questions about timing, type of travel and destination(s). Once these are determined, the potential antimalarial regimen(s) can be reviewed with the traveller (see Appendix I). For many itineraries, there will be several options. Review the advantages and disadvantages (outlined in Table 8.11), and determine what regimen is the best fit for the individual traveller.
2. Select the appropriate dosage of the antimalarial agent, taking time to educate the traveller about proper use of the drug (outlined in Table 8.11).
3. Discuss the importance of PPM, such as insect repellents and bed nets, to help prevent malaria (see Chapter 3).
4. Discuss the importance of seeking out medical advice urgently if the traveller develops a fever while in a malaria-endemic area or within one year^{Footnote a} after returning to Canada.

Selection of antimalarial drugs for specific regions of drug resistance

Travellers should know that, while antimalarial medication can markedly decrease the risk of acquiring symptomatic malaria^{Reference 2}, ^{Reference 4}, ^{Reference 5}, ^{Reference 6}, ^{Reference 7}, ^{Reference 8}, ^{Reference 10} chemoprophylaxis does not provide complete protection. PPM complement antimalarials^{Reference 1} and decrease travellers' risk of acquiring malaria (see Chapter 3).

Although minor differences in expert opinion exist between jurisdictions (i.e. United States, Europe and Canada), experts do agree that chemoprophylaxis is an essential component of malaria prevention in areas of high transmission. Differences in guidelines often relate to preferred regimens or whether to use chemoprophylaxis in areas with low levels of transmission (see below). Such differences might confuse travellers, and practitioners should therefore take care to explain these differences.

Box 4.1 summarizes the main chemoprophylactic options by resistance status (see Chapter 8 for a more complete discussion of these drugs).

Box 4.1: Malaria chemoprophylaxis options by drug resistance status

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 relapse 5 years or more after routine chemoprophylaxis has been discontinued^{Reference 19}, ^{Reference 20}. Although considered less virulent than falciparum malaria, P. vivax still carries the potential for significant morbidity requiring intensive care^{Reference 21}. Since most malaria-endemic areas of the world (except Haiti and the Dominican Republic) have either P. vivax or P. ovale, travellers to these areas have some risk of acquiring relapsing malaria. Primaquine terminal prophylaxis is administered after the traveller has left a malaria-endemic area, usually during or after the post-travel period of chemoprophylaxis. Primaquine decreases the risk of such relapse by acting against the persistent liver stages (hypnozoites) of P. vivax and P. ovale.

Data pertaining to the risk of relapse are limited. One study showed that, of 725 US Army Ranger task force soldiers stationed in Afghanistan, 38 (5.2%) had P. vivax malaria after leaving, 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^{Reference 21}. Military personnel, long-term travellers and expatriates are groups that should be considered for terminal prophylaxis if they were in regions with high P. vivax or P. ovale endemicity. Any traveller who returns to Canada with a history of P. vivax or P. ovale diagnosis should also be considered for terminal prophylaxis^{Reference 22}.

Primaquine is contraindicated in pregnant women and individuals deficient in G6PD (see Chapter 8 for contraindications and precautions).

Differences in approaches to malaria chemoprophylaxis

Committee to Advise on Tropical Medicine and Travel (CATMAT) reviews all major sources of malaria prevention information, including World Health Organization (WHO)^{Reference 23}, Centers for Disease Control and Prevention (CDC)^{Reference 24} and the Health Protection Agency Advisory Committee on Malaria Prevention (ACMP)^{Reference 25}. CATMAT also reviews recent research and national and international epidemiological data in order to provide guidelines and recommendations tailored to the Canadian context. Factors that influence recommendations include: drug licensure, Canadian-specific travel patterns and malaria epidemiology, and the anticipated values and preferences of travellers and health care providers.

Some jurisdictions (e.g. United States) have a very low risk tolerance for malaria in returning travellers^{Reference 24}, and thus give more weight to chemoprophylaxis. Other jurisdictions (e.g. most European countries) emphasize the potential for drug-adverse effects, and are less likely to recommend chemoprophylaxis in low-risk areas. As well, region-specific recommendations are dynamic; thus, some differences arise as a result of the age of the epidemiologic evidence on which the individual recommendation is based. In these guidelines, CATMAT has tried to balance the need for protection with the potential for adverse effects of chemoprophylaxis. For the most part, CATMAT guidelines are consistent with the WHO^{Reference 23} and the CDC's Yellow Book: Health Information for International Travel^{Reference 24}, although there are still some minor differences.

CATMAT recommends chloroquine for the prevention of malaria in chloroquine-sensitive regions. In chloroquine-resistant regions, CATMAT recommends atovaquone-proguanil, doxycycline or mefloquine as three equivalent options for the prevention of malaria. This is similar to the approach of the CDC. Recommendations on when to start and stop malaria chemoprophylaxis are also consistent among major guidelines, and they also 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 (see section on emergency standby treatment for more information).

CATMAT guidelines sometimes differ from WHO and ACMP guidelines with respect to drug recommendations. For example, 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. In addition, in areas with low-to-moderate levels of malaria transmission and with chloroquine resistance (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 first-line chemoprophylaxis. However, CATMAT considers chloroquine-proguanil chemoprophylaxis to be significantly less effective compared with atovaquone-proguanil, doxycycline or mefloquine^{Reference 26}, ^{Reference 27} and does not recommend this regimen.

Emergency standby therapy for short-term travellers is an option that all the guidelines include, although CATMAT and CDC have more restrictive criteria as to when to use it. CATMAT recommends standby self-treatment for selected travellers who are unable to access medical assistance within 24 hours. CDC guidelines recommend atovaquone-proguanil or artemether-lumefantrine for this use, whereas CATMAT recommends standby malaria treatment with atovaquone-proguanil or quinine and doxycycline, since artemether-lumefantrine is not available in Canada. However, CATMAT does not recommend using mefloquine for therapy under any circumstances because of the high likelihood of severe adverse reactions when using higher therapeutic doses. For more information about self-treatment, see Chapter 7.

Discontinuing antimalarial drugs

Fatal malaria has occurred in travellers who have discontinued an effective antimalarial drug in favour of one that is less protective^{Reference 11}, ^{Reference 28}, ^{Reference 29}, ^{Reference 30}. During travel, individuals might meet other travellers and/or health care providers who suggest that they change or stop their antimalarial medication. For the most part, such advice should be ignored or questioned; medications used in other areas of the world may be less effective, may be associated with serious adverse effects or may not be manufactured to Canadian standards and are not recommended for Canadian travellers. Examples include proguanil alone (Paludrine®), pyrimethamine (Daraprim®), dapsone-pyrimethamine (Maloprim®) and mefloquine-sulfadoxine-pyrimethamine (Fansimef®).

One of the exceptions to this general rule is when the traveller is suffering significant adverse events associated with the chemoprophylactic agent. In such a situation, and when the advice is provided by a health care provider (preferably the one who provided the initial advice), changing medication is reasonable. Ideally, this would be to another agent recommended by CATMAT in these guidelines. Discontinuation of all chemoprophylaxis is NOT a reasonable option.

Co-administration 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 co-administered with live attenuated bacterial oral vaccines. Mefloquine and chloroquine have shown in vitro inhibitory activity against an oral typhoid vaccine^{Reference 31}. Proguanil has some antibacterial activity, but co-administering atovaquone-proguanil with live, oral typhoid and cholera vaccines to children did not affect the antibody response to the vaccine^{Reference 32}. However, co-administering of proguanil and chloroquine with live, oral typhoid and cholera vaccines decreased vaccine immunogenicity^{Reference 33}. Vaccine efficacy studies measuring the impact on the incidence of clinical typhoid and cholera of theco-administration of antimalarials with live, oral typhoid and cholera vaccines have not been performed. Since the data are not definitive, the cautious approach will be to complete vaccination with live oral typhoid or cholera vaccines at least 3 days before the first dose of antimalarial medication^{Reference 34}, ^{Reference 35}, ^{Reference 36}. Formalin-and/or heat-inactivated oral vaccines (such as Dukoral®) do not contain live bacteria and may be co-administered with antimalarials.

Concurrent use of chloroquine also interferes with the antibody response to intradermal administration of human diploid cell rabies vaccine^{Reference 37}. If intradermal rabies vaccine is administered to someone taking chloroquine, rabies serology may help confirm response to vaccination, but it is not always easily available.

During the discussion of chemoprophylaxis:

1. Tell travellers that malaria can be fatal, but that medications rarely cause serious adverse events if selected and used with care.
2. Choose a medication that is least likely to exacerbate any past or present medical problem(s).
3. Present all the options to travellers and, unless there is a contraindication, give them a choice of which chemoprophylaxis they prefer; all recommended first-line malaria chemoprophylactic regimens are equally effective.
4. Emphasize that medication should be taken in the recommended fashion to minimize significant adverse events.
5. Discuss the option of a drug trial to check for medication-associated adverse reactions before travelling.
6. Discuss strategies to change medication if serious adverse effects should arise during travel.
7. Advise travellers that if a malaria medication is tolerated well they should continue taking it regardless of negative anecdotes about the drug. There is no evidence to suggest that long- term use of currently recommended therapies for travellers will result in additional risks for severe adverse events.

Table 4.1: Evidence-based medicine recommendations

Recommendation	EBM Rating
Chloroquine (Aralen®) or hydroxychloroquine (Plaquenil®) is the drug of choice for travellers to areas with chloroquine-sensitive malariaReference 11	A I
Atovaquone–proguanil, doxycycline or mefloquine are drugs of choice for travellers to areas with chloroquine-resistant or mefloquine-sensitive malariaReference 2, Reference 4, Reference 5, Reference 6, Reference 7, Reference 8, Reference 10.	A I
Atovaquone–proguanil and doxycycline are drugs of choice for travellers to areas with mefloquine-resistant malariaReference 4, Reference 15, Reference 38.	A I
Primaquine is recommended for malaria chemoprophylaxis for travellers to regions with chloroquine resistance who are not willing or able to use atovaquone–proguanil, doxycycline or mefloquineReference 5.	A I
Primaquine is recommended as post-travel terminal prophylaxis for travellers who have suffered from Plasmodium vivax or Plasmodium ovale malaria while abroadReference 22.	B III
Standby malaria treatment with atovaquone–proguanil or quinine and doxycycline is recommended for travellers who are more than a day away from malaria diagnostic help.	C III
Doxycycline is an antibiotic and should never be co-administered with any live, oral bacterial vaccines. Vaccination with live oral typhoid or cholera vaccines should be completed at least 3 days before the first dose of choloroquine, atovaquone–proguanil or mefloquineReference 34, Reference 35, Reference 36.	B III
Concurrent use of chloroquine interferes with antibody response to intradermal administration of human diploid cell rabies vaccineReference 37. If intradermal rabies vaccine is administered to someone taking chloroquine, it is recommended that post-vaccine rabies antibodies be obtained to verify an adequate immunologic response.	B III
Abbreviation: EBM, evidence-based medicine. Note: For a description of the categories and quality of evidence of the recommendations, see Appendix IV.

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