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


5. Prevention in Special Hosts

Malaria Prevention in Children

Travellers should be clearly advised of the risks in taking young children to areas with P. Falciparum malaria. Many other infectious conditions occur in children that may mimic malaria and delay the diagnosis, but malaria remains an important cause of fever in returning child and adolescent travellers(83, 84). Among Canadians reported to have malaria since 1999, 20% to 25% are ≤ 19 years old(85), whereas only 9.9% of international travellers are aged 19 years (86). As well, severe or complicated malaria, such as cerebral malaria, severe anemia, shock or even death, may develop more quickly in children (87). According to Canadian Malaria Network data from June 2001 to June 2006, 34% of complicated malaria cases requiring treatment with intravenous quinine were in children; the majority were foreign-born(12).

To reduce the risk of infection when travel to malarial areas is unavoidable, all children, including those who are breast-fed, should be well protected against mosquito bites and, when appropriate, receive appropriate malaria chemoprophylaxis (37) if they are at sufficient risk of infection. Infants do not receive sufficient medication through breast milk to protect them and should be prescribed antimalarial drugs even though their mother is receiving them (88, 89). Ensuring that young children take antimalarial drugs may be difficult because of the lack of pediatric formulations and the unpleasant taste. Malaria tablets may be crushed and mixed with chocolate syrup, jam, cereal, bananas or formula to mask the taste. Sufficient tablets should be prescribed to allow for a few doses to be vomited or spat out, with clear instructions as to when doses should be repeated. Pre-cut tablets at the pharmacy and/or crushing and insertion into capsules may help increase the accuracy and ease of dosing. Deaths due to inadvertent overdose have been reported with these medications; therefore, they should be kept out of reach of infants and children and stored in child-proof containers (90). Long-term travelling families should be provided with information to help them adjust the dose of medications, allowing for an increase in weight over time.

Chloroquine remains the preferred agent for chemoprophylaxis in areas with chloroquinesensitive malaria. Although it is not available in Canada, chloroquine sulfate (e.g., Nivaquine) is widely available as a syrup in malaria-endemic areas. The syrup is often more easily administered than tablets. If parents plan to use this syrup they should be informed that the dose must be carefully determined according to the child's weight and that there is a risk of overdosing.

Mefloquine is one of the drugs of choice in chloroquine-resistant regions; however, there are no studies that specifically analyze its bioavailability and rate of metabolism in children. Although the manufacturer recommends that mefloquine not be given to children weighing < 5 kg, it should be considered for prophylaxis of all children at high risk of acquiring chloroquine-resistant P. Falciparum, at a dose of 5 mg base/kg once weekly (91). Young children are less likely to suffer major neuropsychiatric side effects from mefloquine (92) but may be more likely to have emesis (93). While seizure disorders may be exacerbated by chloroquine and mefloquine, and alternative agents should be used, there is no evidence that febrile seizures in children are a contraindication to these drugs.

Atovaquone/proguanil (Malarone®) is licensed for the prophylaxis and treatment of malaria in children ≥ 11 kg (25 lb) or aged > 3 years (68). Clinical trials using atovaquone/proguanil to treat malaria in children down to 5 kg suggest it may be safe for infants of this size when the option is required (94). Daily doses for small infants have been extrapolated from those used in treatment trials (one-quarter of the treatment dose, or 5 and 2 mg/ kg/dose of atovaquone and proguanil components respectively). Based on a pediatric tablet of 62.5 mg atovaquone/25 mg proguanil, the daily doses are ½ pediatric tablet for 5 to 8 kg and ¾ pediatric tablet for > 8 to 10 kg (94).

Doxycycline has been studied as a prophylactic medication in children (95) and can be used at a daily dose of 2 mg/kg (max 100 mg/d) in children ≥ 8 years of age (≥ 25 kg) (88, 96) Primaquine is a consideration for children 9 years of age and older who are unable to take any of the first-line prophylactic agents (58), although it is not licensed in Canada for this indication. As there is no age limitation for primaquine when used for radical cure of P. vivaxor P. ovale maybe it is an option for children of any age as long as they have been screened for adequate G6PD levels. Consultation with a travel medicine or infectious disease expert is advisable unless the prescriber has experience with this medication in the pediatric population.

Evidence-based medicine recommendations EBM rating

Young children should avoid travel to areas with significant transmission particularly of chloroquine-resistant malaria (88).

Effective personal protective measures should be strongly encouraged for all children who travel to malaria-endemic areas (38). A I
For children travelling to or residing in chloroquine-resistant areas, mefloquine, doxycycline (≥ 8 yrs) and atovaquone/proguanil (≥ 5 kg) are the drugs of choice for chemoprophylaxis (68, 91, 95, 97). A I

Primaquine chemoprophylaxis is a consideration for children who are unable to take any of the first-line prophylactic agents (58).


Malaria Prevention in Pregnancy

Malaria increases the risk of maternal and neonatal death, miscarriage and stillbirth. In addition, low birth weight infants are more frequent among women who are taking ineffective prophylaxis (98). Pregnant women should defer travel to malaria- endemic areas, particularly to areas with risk of acquisition of drug-resistant Falciparum malaria. Pregnant women are twice as likely to be bitten by mosquitoes, thought to be the result of increased body surface temperature, increased CO2 production and increased likelihood of leaving the protection of the bednet at night (99). If travel cannot be avoided, special care should be taken, including the use of DEET, which has been shown to be safe in pregnancy, to avoid mosquito bites (100). In addition, effective chemoprophylaxis should be selected as outlined below.

Doxycycline is contraindicated for malaria prophylaxis during pregnancy because of adverse effects on the fetus, including discoloration and dysplasia of the teeth, and inhibition of bone growth. Attempts to become pregnant should be avoided for a week after completing prophylaxis using doxycycline to allow for complete excretion. Primaquine is also contraindicated during pregnancy (category C - since the G6PD status of the fetus cannot be established and the drug can be passed transplacentally (96). Whenever radical cure or terminal prophylaxis with primaquine is indicated in a pregnant woman, chloroquine can be given once a week until delivery, at which time primaquine may be given (see next section on breast-feeding).

Proguanil has long been known to be safe in pregnancy; however, data are lacking on atovaquone. Small malaria treatment trials using atovaquone/ proguanil (Malarone®) alone or with artesunate have included women in the second and/or third trimesters of pregnancy. Drug tolerability was good, as were the birth outcomes (93, 101). Until these data are supported with further trials or experience, atovaquone/ proguanil is not routinely recommended during pregnancy. However, when other options cannot be used and the potential benefit outweighs the potential risk to the fetus, it may be considered after the first trimester.

Mefloquine can be used safely for chemoprophylaxis through most of pregnancy. While treatment doses (≥ 5-fold greater than doses for prophylaxis) may be associated with an increased risk of stillbirth (102), the majority of observational and clinical trial data have concluded that the drug does not lead to an increased risk of either stillbirth or congenital malformations at prophylactic doses used during the second and third trimesters (102, 103, 104). Surveillance data of >1,500 pregnant women found no evidence of increased risk of either teratogenicity or spontaneous abortion when the drug was used at any time from before conception up to and including the third trimester (105). Although there does not appear to be a concern early in pregnancy, the data are limited before the second trimester. While the use of mefloquine at the time of conception or during the first trimester is not an indication for therapeutic abortion (103, 106), highly risk-averse travellers may choose to avoid pregnancy for up to 3 months after discontinuing mefloquine because of the long half-life of the drug (~3 wks). For expatriates or other long-term travellers in malaria- risk areas, it is safer for both fetus and mother to use effective chemoprophylaxis, given the ongoing risk of disease and the increased risk of severe disease and death during pregnancy (98).

While chloroquine and proguanil are both safe in pregnancy, the combination is ineffective in preventing chloroquine-resistant P. Falciparum and is not recommended.

Evidence-based medicine recommendations EBM rating

If possible, pregnant women should avoid travel to areas with significant transmission of malaria (98).

Personal protective measures, including the appropriate use of DEET and pyrethroid-impregnated bednets, are safe and should be strongly encouraged for all pregnant women who travel to malaria-endemic areas (100). A I
Pregnant women travelling to or residing in chloroquine-sensitive areas should use chloroquine as chemoprophylaxis. A I
Mefloquine is recommended where exposure to chloroquine-resistant Falciparum malaria is unavoidable from conception through the first trimester (A II), as well as the second and third trimesters (A I) (102, 103, 104). A II,
There are no currently approved drugs to prevent malaria in pregnant women travelling to mefloquine-resistant regions. Atovaquone-proguanil (Malarone® ) after the first trimester in women who cannot avoid travel to mefloquine-resistant areas (e.g., border areas between Thailand and Cambodia/Myanmar) may be considered after careful discussion of the benefits and risks (93, 101). B II

Although safe in pregnancy, chloroquine and proguanil are inadequate and cannot be recommended in chloroquine-resistant areas (107).


Prophylaxis While Breast-Feeding

The availability of antimalarial medication in breast milk is insufficient to provide protection against malaria; therefore, infants requiring chemoprophylaxis should receive a recommended dose of appropriate antimalarial drug. Breast-feeding is not a contraindication for the use of medications that are safe in infancy (chloroquine, mefloquine, atovaquoneproguanil in infants ≥ 5 kg). There is no information on the amount of primaquine that enters human breast milk; therefore, the infant should be tested for G6PD deficiency before primaquine is given to a woman who is breast-feeding. Because of the lack of data on the safety and efficacy of atovaquone in infants weighing < 5 kg, atovaquone/proguanil should not be given to a woman who is breast-feeding an infant of this size unless the potential benefit to the woman outweighs the potential risk to the infant. Limited data are available on the safety of doxycycline use during breastfeeding, but the American Academy of Pediatrics states that no observable effect has been noted in infants of lactating women using tetracyclines, and absorption by the infant is negligible(108).

Evidence-based medicine recommendations EBM rating

Infants who are at risk of malaria and who are being breast-fed should receive their own appropriate chemoprophylaxis(94).

Atovaquone-proguanil should be avoided if possible in a woman who is breast-feeding a child < 5 kg(94). C II
Limited data suggest that doxycycline absorption through breast milk is negligible and that breast-feeding is not an absolute contraindication to maternal use(108). C III

Malaria Prevention in the Long-Term Traveller or Expatriate

Modern prevention strategies have had a significant, positive impact on the risk of mortality in long-term expatriates, reported to be as high as 60% among missionaries in West Africa during the 19th century(109). However, the effort to develop unique, evidenced- based guidelines for the long-term (> 6 months) traveller or expatriate has been limited by a lack of medical literature in this area.

Concerns encountered when addressing malaria prevention in long-term travellers and expatriates include safety of the drugs used for chemoprophylaxis, fear of toxic effects with prolonged use of medication, conflicting counsel regarding appropriate chemoprophylaxis and self-treatment, and lack of adherence to chemoprophylaxis, as well as the use of personal protective measures.

The advice of health consultants competes with the opinions of those who assume that their personal experience with adverse events is representative of the general population(110). Some researchers have observed that the incidence of malaria may be greater among veteran expatriates when compared with their less experienced counterparts. The veterans may have an unreasonable confidence in their clinical self-diagnosis(111) compounded by the impact of false-positive laboratory errors(112). Counterfeit drugs can also lead to the impression that failure of response is attributed to drug resistance.

Adverse events

At present, there is no evidence to suggest that long-term use of therapies currently recommended for short-stay travellers will result in additional risk of severe adverse events. Chloroquine may be an exception; however, this drug is seldom indicated currently because of extensive drug resistance. Chloroquine retinopathy is an adverse event experienced by up to 16% of persons using chloroquine treatment for rheumatoid arthritis at a dose far exceeding that used for malaria prophylaxis( 113). However, the cumulative dose may still predispose one to the risk of retinopathy(114, 115). Lange et al. explored the correlation between the total body burden of chloroquine and the development of retinopathy among 53 missionaries who had taken a median cumulative dose of 300 g(116). This study failed to demonstrate any association between a weekly chloroquine dosing regimen and retinopathy; however there is a single case report of an expatriate with retinopathy after a cumulative dose of 125 g over 8 years(117). Although the data supporting long-term use of doxycycline for chemoprophylaxis are limited, the drug is in use for extended periods of time for other indications.

It has been observed that mefloquine tolerance has improved over time, perhaps associated with the relatively early onset of adverse events experienced by those who use mefloquine for prophylaxis(112).

Current malaria prevention practice among expatriates

Malaria chemoprophylaxis use in expatriates is suboptimal. A self-reported summary of malaria prevention strategies of 1,192 long-term expatriates, representing a broad range of government and non- government organizations in sub-Saharan Africa, indicated that their compliance rate was approximately 60% (unpublished data, K. Gamble). Of those receiving chemoprophylaxis, 54% reported changing their prophylactic regimen, 22% because of adverse effects. The severity of side effects was not associated with any specific drug, but the reported incidence of neuropsychiatric side effects was 10% among persons taking chloroquine and proguanil compared with 17% in the mefloquine group. Mefloquine was the only regimen for which participants reported a change in practice based on media influence. Only a small number indicated that availability and cost were factors in their choice of prophylactic regimens. Participants who did not use prophylaxis cited concerns about adverse reactions and long-term effects as the primary reasons for their choice. Personal protective measures were suboptimal: only 38% had screened doors and windows, and 53% used mosquito netting (20% of which were insecticide-treated nets).

Of 336 Canadian expatriates at risk of malaria in tropical countries, only 56% were in compliance with Canadian guidelines, 6.7% did not take any prophylaxis, and 3% asserted that they were not able to tolerate available options (unpublished data, K. Gamble). This is comparable to the outcome of an anonymous, post-deployment survey of US Army Rangers in 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, 82% for treating uniforms with permethrin and 29% for the application of insect repellent(73).

Support for established guidelines

In general, guidelines for the prevention of malaria in long-term travellers or expatriates should not deviate significantly from standard recommendations for the short-term traveller, though cost will likely limit the use of atovaquone/proguanil.

Data on the incidence of malaria and the effectiveness and tolerance of currently recommended regimens for long-term travellers are limited. Studies of Peace Corps volunteers and studies conducted in chloroquineresistant regions consistently demonstrate that long- term use of mefloquine is well tolerated and is more effective than chloroquine and proguanil(57, 77, 112, 118). There is some evidence that better education of travellers has compliance benefits. The incidence of malaria in a cohort of expatriates in Ghana ranged from 1/50 to 1/25 per month between 1993 and 1999 (2%-4%). A malaria prevention program was instituted that included instruction on Canadian guidelines, personal protective measures and self- treatment with self-administered positive rapid diagnostic tests. Surveillance data indicated that the monthly incidence of malaria decreased from 4/1000 in 2000 to 1.7/1000 in 2002 (0.4-0.17%) (unpublished data, K. Gamble).

Insecticide-treated bednets

Long term travellers face challenges in personal protection that differ from those of short-term travellers, and these are addressed in Chapter 3. Education about seasonal changes in weather and malaria risk need attention. Rainy seasons require the renewal of the insecticide in bednets, because most long-term travellers are using nets whose insecticide loses its effect after 6 months of use. Liquid permethrin is not available in Canada and must be acquired abroad. The availability of long- lasting insecticide-treated nets in some European countries is an option that can be explored(119).

Rapid diagnostic tests (RDTs)

Without training, there is no reason to believe that the usefulness of these will be any better than that demonstrated in the general travel population(120, 121) (see Chapter 7 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 as there are no data available from controlled studies on the use of RDTs in the long- term traveller or expatriate populations.

Counterfeit Drugs

The production, distribution and sale of counterfeit antimalarial, antiretroviral and other medications are widespread throughout many parts of the Orient, Asia and Africa(122, 123, 124). One-third to one-half of artesunate tablets in Southeast Asia were found to have no active ingredient. Many expatriates purchase their antimalarial drugs over the counter, and they do not have the capacity to evaluate the authenticity of these drugs. Encouragement to purchase brand names may not be adequate(122, 123, 124).

All travellers, and especially long-term travellers, expatriates and missionaries, should be warned about counterfeit drugs. If Coartem® , which is not yet licensed for distribution in Canada but is recommended by the WHO as first-line treatment for Falciparum malaria in Africa, is to be recommended, it should be purchased in countries where counterfeiting is unlikely (e.g. Europe). Although atovaquone/ proguanil prophylaxis is too expensive for most long-term travellers and expatriates, most could afford one or two courses to ensure that self- treatment is readily accessible.

The counterfeit drug problem is especially important for long-term travellers because they will be dependent for renewal of their antimalarial chemoprophylaxis prescriptions and for stand-by malaria self- treatment drugs from pharmacies in countries where counterfeiting is a problem(122, 123, 124).

Many expatriates purchase their antimalarial drugs over the counter, and they do not have the capacity to evaluate the authenticity of the drugs that they acquire. Counsel to purchase brand names may not be adequate. All expatriates and long-term travellers should be warned about counterfeit drugs and should be encouraged to purchase a supply of medication in countries where strict quality control measures are in place.

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 – Chemoprophylactic Regimens for details.

Evidence-based medicine recommendations EBM rating

Guidelines for the prevention of malaria in long-term travellers or expatriates should not deviate significantly from recommendations for short-term travellers(125).

Training in the use of rapid diagnostic tests is reasonable for long-term travellers(120, 125). C III
Education about counterfeit antimalarial medications is important for long-term travellers who are more likely to purchase drugs in countries without controls(122, 123, 124). C II
Primaquine should be considered for terminal prophylaxis (see Chapter 8) for military personnel, long-term travellers or expatriates who return from regions with P. vivaxtransmission(73, 125, 126). A I

Malaria Prevention in Travellers with Co-morbidities

Travellers with underlying medical conditions present a special challenge for a wide variety of reasons. These include the potential for increased susceptibility to and severity of malaria, the deleterious impact of malaria on the underlying condition and the complexity of potential interactions between antimalarials and other medications.

Immunocompromised hosts

  1. HIV/AIDS: Recent data suggest a two-way relationship between human immunodeficiency virus (HIV) and P. Falciparum; each has a deleterious effect on the other. Malaria infection stimulates HIV-1 replication, resulting in increased viral loads that persist for weeks after the infection, although the impact on disease progression is not yet clear(127, 128). Conversely, it has been shown that those infected with HIV have an increased risk of parasitemia and clinical malaria infection compared with HIV-negative individuals. Mathematical modeling suggests large numbers of excess HIV and malaria infections, possibly a result of these interactions. Malaria infection risk and parasite density increase as the immune status deteriorates(128) and appear to be worse in non- immune, non-pregnant individuals than in those with partial immunity(21). Although the greatest risk of adverse birth outcomes in partially immune women is usually in the first pregnancy, in those with HIV co-infection this risk is spread to all pregnancies(129).
  2. Women who are co-infected with HIV may have a higher risk of mother-to-child HIV transmission as a result of disruption of placental architecture(130). Unfortunately, malaria treatment failure is greater among HIV-infected adults than HIV-negative adults(131). Treatment of HIV often includes multiple antiretroviral drugs, several of which (particularly non-nucleoside reverse transcriptase inhibitors and protease inhibitors) may interact with antimalarial drugs, resulting in toxicity from or reduced effec-tiveness of either drug(132). Overlapping adverse effect profiles may also be problematic(133). Various antiretroviral drugs may have direct or indirect antimalarial activity, although the clinical utility has yet to be determined(134). Consultation with a travel or tropical medicine expert in conjunction with the traveller's HIV-specialist is advised.

  3. Asplenia: The spleen facilitates phagocytosis and promotes removal of parasitized red blood cells. Delayed clearance of parasites has been demonstrated in asplenic patients despite the use of effective malaria therapy(135). Splenectomy increases the risk and magnitude of parasitemia, even among partially immune individuals in malaria-endemic countries(136), and severe malaria has been reported in travellers with asplenia(137). Standby self-treatment should be considered in addition to prophylactic measures if remote regions are being visited and/or access to care is limited (see Chapter 6). Fever in an asplenic individual may represent malaria or infection with an encapsulated bacterial organism, so antibacterial standby treatment should also be discussed(132).
  4. Other immunosuppressive conditions: There is limited information about the natural history of malaria in individuals with other immunocompromising conditions. The clinical course of malaria in these individuals is presumably similar to or worse than in other individuals. However, the practitioner must also consider any immunosuppressive medications that are being used, many of which are metabolized in the liver by the microsomal enzymes and thus may interact with certain antimalarial medications. A travel or tropical medicine expert should work closely with the specialist caring for such travellers to advise appropriately.

Other conditions

  1. Cardiovascular: Although mefloquine has been reported to cause arrhythmias when used for pro- phylaxis(138), this has not been confirmed with small studies of the drug in volunteers(139). There are reports of mefloquine, doxycycline and proguanil potentiating warfarin, resulting in abnormal coagulation and sometimes bleeding(139, 140, 141, 142, 143). If these medications are used (including proguanil as a component of Malarone® ), a medication trial should be done several weeks in advance in order that serial testing of the International Normalized Ratio (INR) can be done to allow adjustment of the anticoagulant dose.
  2. Neuropsychiatric: Seizure disorders may be exacerbated by chloroquine and mefloquine, so alternative agents should be used. There is no evidence that febrile seizures in children are a contraindication for these drugs. Concurrent use of anticonvulsant drugs that induce hepatic microsomal enzymes (e.g., barbiturates, phenytoin, carbamazepine) may decrease serum levels and half-life of doxycycline, and may require a dosage adjustment(143) (see Chapter 8. Mefloquine may be associated with an increased risk of psychiatric conditions, including depression and anxiety disorders, and therefore careful history- taking is needed to rule out such conditions before mefloquine is used(144). There are no data demonstrating that attention deficit disorder increases the risk of neuro-psychiatric side effects; however, it is prudent to ensure that psychiatric conditions such as those noted above do not co-exist(93).
  3. Hepatic or renal dysfunction: Moderate to severe hepatic or renal dysfunction may result in significant alteration in antimalarial medication levels. If either the liver or kidneys are compromised, there must be careful consideration given to the selection and dose of medications for the prophylaxis and treatment of malaria. If the course of action is unclear after review of a standard reference, consultation with a travel medicine expert is recommended.
Evidence-based medicine recommendations EBM rating

Individuals who are immunosuppressed or have other co-morbidities should consult with a travel medicine or infectious disease expert in conjunction with the principal physician for their underlying condition(20).

Potential drug interactions warrant careful review before antimalarial drugs are prescribed for an HIV-infected individual(133). A I
An advance trial with INR testing should be done if mefloquine, doxycycline or proguanil (including atovaquone-proguanil) are to be used in individuals taking warfarin(140, 141, 142, 143). A II
Mental health conditions should be carefully elicited to ensure that psychotic, depressive or anxiety disorders are absent before mefloquine use is considered(144). A I


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