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Malaria Prevention
Malaria is the most important parasitic disease in the world. Human malaria is a blood-borne protozoal infection caused by five species of the genus Plasmodium : P. falciparum , P. vivax , P. ovale , P. malariae , and P. knowlesi . The infection is transmitted through the bite of infected female Anopheles mosquitoes. Less commonly, malaria may be transmitted by blood transfusion, with shared needle use, or congenitally, from mother to fetus. Ecologic change and economic and political instability, combined with escalating malaria drug resistance, have led to a worldwide resurgence of this parasitic disease. The 2014 World Malaria Report (World Health Organization [WHO] and United Nations Children's Fund [UNICEF]) estimated there were more than 220 million cases and more than 600,000 deaths annually resulting from malaria.
Malaria is not just a problem in the developing world, however. The combination of increases in international travel and increasing drug resistance has resulted in a growing number of travelers at risk of contracting malaria. It is estimated that as many as 30,000 travelers from industrialized countries contract malaria each year. However, this incidence is likely to be an underestimate because of the failure to take into account those who are diagnosed and treated abroad and the prevalence of underreporting. The majority of P. falciparum cases imported into North America and Europe are acquired in Africa (85%), and travel to the African continent is still on the rise.
The overall case fatality rate of imported P. falciparum malaria varies from 0.6 to 3.8% but may be much higher in the elderly. The fatality rate of severe malaria may be ≥20% even when managed in modern intensive care units; however, cases of imported malaria and associated fatalities remain largely preventable, provided high-risk travelers use appropriate chemoprophylaxis and measures to reduce insect bites, and physicians promptly recognize infections and initiate appropriate treatment.
Approach to Malaria Prevention
This chapter highlights the important principles of malaria prevention. The interested reader is referred to Table 6.1 and the references for additional sources of information and country-specific malaria risk. There are four principles—adapted from the WHO's ABCD of malaria protection—of which all travelers to malarious areas should be informed:
- A
Be A ware of the risk and the symptoms and understand that malaria is a serious infection.
- B
Avoid mosquito B ites.
- C
Take C hemoprophylaxis when appropriate.
- D
Seek immediate D iagnosis and treatment if fever develops during or after travel.
TABLE 6.1
Internet Resources for Travel Health Information and Country-Specific Malaria Risk
| http://www.cdc.gov/travel/ US Centers for Disease Control and Prevention (Travelers' Health Section) |
On-line references include full text of Health Information for International Travel 2016, with full adult and pediatric recommendations, including malaria risks and recommendations. |
| http://www.who.int/ith/en WHO (International Travel and Health Information Resource Page) |
Includes updates on country-specific malaria risk. |
| www.TravelHealth.gc.ca Health Canada (Travel Medicine Resource Page) |
See Information for Travel Medicine Professionals. Contains CATMAT guidelines, travel bulletins, and updates for preventing and treating malaria in travelers. |
CATMAT, Committee to Advise on Tropical Medicine and Travel.
These principles, which are key issues to be considered when advising travelers on protection against malaria, are discussed in further detail below and summarized as a checklist in Table 6.2 .
TABLE 6.2
Checklist for Travelers to Malarious Areas
Adapted from World Health Organization, 2012, International Travel and Health.
The following is a checklist of key issues to be considered in advising travelers.
|
Protection against malaria can be summarized into the following four principles.
1
Assessing Individual Risk
Estimating a traveler's risk is based on a detailed travel itinerary and specific risk behaviors of the traveler (examples in parentheses represent increasing risk). The risk of acquiring malaria varies according to the geographic area visited (e.g., Southeast Asia vs. Africa), the travel destination within different geographic areas (urban vs. rural travel), type of accommodations (well screened or air conditioned vs. camping), duration of stay (1-week business travel vs. 3-month overland trek), season of travel (low vs. high malaria transmission season), and elevation of destination (malaria transmission is rare above 2000 m). In addition to the location, travelers can influence their own risk by how well they comply with preventive measures, such as treated bed nets and chemoprophylactic drugs, and the efficacy of these measures.
Additional information can be obtained from studies using malaria surveillance data that estimate risk of malaria in travelers. For example, relative risk assessments show that travelers are 207 times more likely to acquire malaria in sub-Saharan Africa compared with low-risk areas, and the relative risk decreases with other destinations studied such as South Asia (53.8), Central America (37.8), Southeast Asia (11.5), and South America (8.3). Risk of infection if no chemoprophylaxis is used varies from >20% per month in regions of Papua (formerly Irian Jaya) to 1.7-2.4% per month in West Africa to 0.01% per month in Central America. Of note, the estimated risk of malaria for travelers to Thailand in one study was 1 : 12,254, which may be less than the risk of a serious adverse event secondary to malaria chemoprophylaxis. Such data can also help provide an estimate of the cost/benefit ratio for the use of various chemoprophylactic drugs in different geographic areas. Good sources of updated malaria information and country-specific risk are available online from the WHO, Centers for Disease Control and Prevention (CDC), and Health Canada ( Table 6.1 ).
2
Preventing Mosquito Bites (Personal Protection Measures)
All travelers to malaria-endemic areas need to be instructed in how best to avoid bites from Anopheles mosquitoes that transmit malaria. Any measure that reduces exposure to the evening and nighttime feeding female Anopheles mosquito will reduce the risk of acquiring malaria. Different brands of effective insect repellents are available, but some should not be used on babies and small children. Insecticide-impregnated bed nets (with permethrin or other chemicals) are safe for children and pregnant women and are—together with use of repellents—an effective prevention strategy that is underused by travelers. Additional details are provided in Chapter 1 .
3
Use of Chemoprophylactic Drugs Where Appropriate
The use of antimalarial drugs and their potential adverse effects must be weighed against the risk of acquiring malaria (as described previously). The following questions should be addressed before prescribing any antimalarial drug:
- a.
Will the traveler be exposed to malaria?
- b.
Will the traveler be in a drug-resistant P. falciparum zone?
- c.
Will the traveler have prompt access to medical care (including blood smears prepared with sterile equipment and then properly interpreted) if symptoms of malaria were to occur?
- d.
Are there any contraindications to the use of a particular antimalarial drug?
An overview of antimalarial drug regimens based on drug-resistance zones is provided in Figure 6.1 and Table 6.3 . It is important to note that a number of travelers to low-risk areas, such as urban areas and tourist resorts of Southeast Asia, continue to be inappropriately prescribed antimalarial drugs that result in unnecessary adverse events but offer little protection. Improved traveler adherence with antimalarial drugs is more likely when travel medicine practitioners make a concerted effort to identify and carefully counsel the high-risk traveler and avoid unnecessary drugs in the low-risk individual.
TABLE 6.3
Malaria Chemoprophylactic Regimens for At-Risk Individuals According to Zones of Drug-Resistance a
| Zone | Drug(s) of Choice b | Alternatives |
|---|---|---|
| No chloroquine resistance | Chloroquine | Doxycycline or atovaquone-proguanil |
| Chloroquine resistance | Atovaquone-proguanil or doxycycline or mefloquine c | Primaquine d |
| Chloroquine and mefloquine resistance | Atovaquone-proguanil or doxycycline | |
| Adult doses | ||
| Atovaquone-proguanil | One tablet daily | |
| Chloroquine phosphate | 300 mg (base) weekly | |
| Doxycycline | 100 mg daily | |
| Mefloquine | One tablet weekly (250 mg salt in the United States; base elsewhere) | |
| Primaquine | 30 mg (base) daily d | |
Note : Protection from mosquito bites (insecticide-treated bed nets, N , N -diethyl-meta-toluamide [DEET]-based insect repellents, etc.) is the first line of defense against malaria for all travelers. In the Americas and Southeast Asia, chemoprophylaxis is recommended only for travelers who will be exposed outdoors during evening or night time in rural areas.
a See detailed information in Table 6.4 .
b Chloroquine and mefloquine are to be taken 1-3 weeks before entering malarial areas, continued during the stay in malarial areas, and taken for 4 weeks after leaving malarial areas. Doxycycline may be started 1 day before entering malarial areas but must be continued for 4 weeks after departure. Atovaquone-proguanil and primaquine are started 1 day before entering the malarial area and may be discontinued 7 days after leaving the malaria-endemic area.
c Adhere to boxed warning about contraindications before prescription.
d Contraindicated in glucose-6-phosphate dehydrogenase (G6PD) deficiency and during pregnancy. Not presently licensed for this use. Must perform the G6PD level test before prescribing.
4
Seeking Early Diagnosis and Treatment If Fever Develops during or after Travel
Travelers should be informed that although personal protection measures and antimalarial drugs can markedly decrease the risk of contracting malaria, these interventions do not guarantee complete protection. Symptoms resulting from malaria may occur as early as 1 week after first exposure and as late as several years after leaving a malaria zone, whether or not chemoprophylaxis has been used. Most travelers who acquire falciparum malaria will develop symptoms within 2 months of exposure. Falciparum malaria can be effectively treated early in its course, but delays in therapy may result in a serious and even fatal outcome. The most important factors that determine outcome are early diagnosis and appropriate therapy. Travelers and healthcare providers alike must consider and urgently rule out malaria in any febrile illness that occurs during or after travel to a malaria-endemic area (see Chapters 20 and 21 ).
Current Chemoprophylactic Drug Regimens
Antimalarial drugs are selected based on individual risk assessment (as discussed previously) and drug-resistance patterns ( Figs. 6.1 , 6.2 , and Tables 6.1, 6.3, and 6.4 ). Chloroquine-resistant P. falciparum (CRPF) is now widespread in all malaria-endemic areas of the world, except for Mexico, the Caribbean, Central America, Argentina, and parts of the Middle East and China. P. falciparum malaria resistant to chloroquine and mefloquine is still rare except on the borders of Thailand with Cambodia and Myanmar (Burma). Resistance to sulfadoxine-pyrimethamine is now common in the Amazon basin and Southeast Asia and is increasing in many regions of Africa. Chloroquine-resistant P. vivax is also becoming an important problem, particularly in Papua New Guinea, Papua (formerly Irian Java), Vanuatu, Myanmar, and Guyana. More recently P. knowlesi has been indentified in Southeast Asia as causing clinical malaria resembling falciparum malaria.
TABLE 6.4
Antimalarial Drugs, Doses, a and Adverse Effects (Listed Alphabetically)
| Generic Name | Packaging | Adult Dose | Pediatric Dose | Adverse Effects |
|---|---|---|---|---|
| Artemether/Lumefantrin | 20 mg Artemether and 120 mg Lumefantrine in 1 tablet | Prevention: not indicated
|
Prevention: not indicated Treatment: Licensed from 5 kg body weight. Total treatment: 6 doses (initially, then after 8, 24, 36, 48, and 60 hours)
|
Frequent: GI symptoms, headache, dizziness Rare: QTs prolongation, cardiac arrhythmia, hemolysis |
| Atovaquone- proguanil | 250 mg atovaquone and 100 mg proguanil (adult tablet) |
|
|
|
| Chloroquine b phosphate | 150 mg base |
|
|
|
| Doxycycline d | 100 mg |
|
|
|
| Mefloquine | 250 mg base |
|
|
|
| Quinine | 330 mg salt |
|
|
|
| Primaquine ( Note : Must perform G6PD testing before use) | 15 mg base |
|
|
|
G6PD, Glucose 6-phosphate dehydrogenase; GI, gastrointestinal.
a Dose for chemoprophylaxis, unless specified for “Treatment.”
b Chloroquine sulfate (Nivaquine) is not available in the United States and Canada but is available in most malaria-endemic countries in both tablet and syrup form.
c Generally, 2 tablets twice per day on days 1 and 2, then 2 tablets on day 3 (total of 10 tablets).
d For treatment only in combination with other antimalarials.
e Doses increased to 30 mg base/day due to primaquine-resistant/tolerant P. vivax .
f Doses increased to 0.5 mg base/kg/day due to primaquine-resistant/tolerant P . vivax .
Chloroquine-Sensitive Zones
Chloroquine is the drug of choice for travel to areas where chloroquine resistance has not been described. Chloroquine is active against the erythrocytic forms ( Fig. 6.3 ) of sensitive strains of all species of malaria, and it is also gametocidal against P. vivax , P. malariae , and P. ovale . Except for its bitter taste, chloroquine is usually well tolerated and has a low incidence of serious adverse events. Dark-skinned persons may experience generalized pruritus that is not indicative of drug allergy. Retinal toxicity that may occur with long-term high doses of chloroquine used in the treatment of other diseases is extremely unlikely with chloroquine given as a weekly malaria chemosuppressive agent. Chloroquine use is suitable for people of all ages and for pregnant women. Because insufficient drug is excreted in breast milk to protect the infant, nursing infants should be given chloroquine. Contraindications include people who are glucose 6-phosphate dehydrogenase (G6PD) deficient or hypersensitive to 4-aminoquinoline compounds. Administration of the oral live typhoid vaccine and live cholera vaccine should be completed 3 days before chloroquine use, and chloroquine may suppress the antibody response to primary pre-exposure rabies vaccine.
Chloroquine-Resistant Zones
For many travelers to these areas, a choice between atovaquone-proguanil (AP) (e.g., Malarone™), doxycycline (e.g., Vibramycin™), or mefloquine (e.g., Lariam™), will have to be made. Less commonly primaquine may be used. Deciding which agent is best requires an individual assessment of risk of malaria and the specific advantages and disadvantages of each regimen ( Table 6.5 ). For drugs such as mefloquine and doxycycline to be optimally effective, they need to be taken for 4 weeks after leaving a malaria-endemic area, although traveler adherence with this component has been traditionally poor. Agents such as AP and primaquine are called causal prophylactics because they kill malaria early in its life cycle in the liver, and therefore may be discontinued 1 week after leaving an endemic area ( Fig. 6.3 ). This advantage makes these drugs attractive for high-risk but short-duration travel. It is important to note that none of these agents is ideal, and all carry a risk of adverse events that are distressing enough to travelers that 1-7% will discontinue their prescribed chemoprophylactic regimen. 
TABLE 6.5
Clinical Utility Score for Current Malaria Chemoprophylactic Regimens
Note : Scores and weighting are arbitrary and can be modified/individualized to specific travelers and itineraries.
a Efficacy: 1, <75%; 2, 75-89%; 3, ≥90%.
b Tolerance: 1, occasional disabling side effects; 2, rare disabling side effects; 3, rare minor side effects.
c Convenience: 1, daily and weekly dosing required; 2, daily dosing required; 3, weekly dosing required.
d Causal: 0, no causal activity; 2, causal prophylactic (may be discontinued within a few days of leaving risk area).
e Cost: 1, >US$100/month; 2, US$50-100/month; 3, <US$50/month.
f Requires a pre-travel G6PD measurement, resulting in a lower convenience score.
Atovaquone Plus Proguanil (Malarone)
Malarone is a fixed-dose combination of atovaquone and proguanil hydrochloride. AP works against the erythrocytic stages of all the Plasmodium parasites and the liver-stage (causal prophylaxis) of P. falciparum . The AP combination is effective against P. falciparum malaria strains that are resistant to a variety of other antimalarial drugs.
Atovaquone inhibits parasite mitochondrial electron transport at the level of the cytochrome bc1 complex and collapses mitochondrial membrane potential. The plasmodial electron transport system is 1000-fold more sensitive to atovaquone than the mammalian electron transport system, which likely explains the selective action and limited side effects of this drug. Proguanil is metabolized to cycloguanil, which inhibits dihydrofolate reductase and impedes the synthesis of folate cofactors required for parasite DNA synthesis. AP works synergistically since proguanil, which alone has no effect on mitochondrial membrane potential or electron transport, significantly enhances the ability of atovaquone to collapse mitochondrial membrane potential; however, this is not mediated through the cycloguanil metabolite. This might explain why proguanil enhances atovaquone activity even in the presence of documented cycloguanil resistance or in patients deficient in the cytochrome P450 enzymes required for the conversion of proguanil to cycloguanil.
In randomized, controlled trials, AP was highly efficacious in preventing P. falciparum malaria in both adults and children. Four published trials have examined the protective efficacy of AP in semi-immune adults and children living in malaria-endemic areas. The overall efficacy of AP in the prevention of P. falciparum malaria in these trials was 98% (95% CI 91.9-99.9%). The protective efficacy of AP for prevention of P. falciparum malaria in non-immune adults and children has been examined in five clinical trials, four of which were randomized, and three blind. Collectively, the protective efficacy of AP was 96-100% (95% CI 48-100%). Only one randomized, double-blind, placebo-controlled trial has evaluated the protective efficacy of AP against P. vivax . The protective efficacy of AP was 84% (95% CI 45-95%) for P. vivax and 96% (95% CI 71-99%) for P. falciparum . As AP does not appear to eradicate P. vivax hypnozoites, it is suggested that travelers to areas where the transmission rates of P. vivax are high should receive consideration for presumptive antirelapse therapy with primaquine.
Controlled trials indicate that AP at prophylactic doses is well tolerated by adults and children with drug discontinuation rates of 0-2%. The most commonly reported adverse events are headache and abdominal pain (which can often be reduced by taking AP with food); however, in placebo-controlled trials, these occurred at similar rates as in placebo recipients. In two large randomized, double-blind clinical trials in non-immune subjects traveling to a malaria-endemic area, chemoprophylactic drugs were well tolerated, but AP was significantly better tolerated than either mefloquine or chloroquine/proguanil (CP) in these studies. Participants receiving AP reported significantly lower rates of neuropsychiatric adverse events (14% vs. 29%) compared with mefloquine, significantly lower gastrointestinal adverse events (12% vs. 20%) compared with CP, and lower drug discontinuation rates compared with both. In another randomized trial in travelers, AP was the best-tolerated chemoprophylactic with discontinuation rates of 1.8% versus 3.9% for mefloquine and doxycycline and 5.2% for CP. Additionally, efficacy and tolerability have been examined in pediatric travelers using a randomized comparative trial of AP versus CP. There were no prophylactic failures, but AP was better tolerated with no premature discontinuation of AP due to an adverse event, compared with a 2% discontinuation rate with CP.
AP is currently indicated for the prophylaxis and treatment of P. falciparum malaria including areas where chloroquine and/or mefloquine resistance has been reported. Travelers who have experienced intense exposure to P. vivax and P. ovale should be considered for radical treatment with primaquine on leaving the malaria-endemic area. Because of its causal activity, AP is taken 1 day prior to travel in a malarious zone, daily while exposed, and for 7 days on leaving.
AP is contraindicated in those with severe renal impairment and in those with a history of hypersensitivity to any of the drug components. AP is currently approved for the prevention of malaria in children >5 kg and adults in the United States, Australia, and Europe. A lack of data exists for the use of AP during pregnancy or breast feeding, and it is not currently recommended for chemoprophylaxis. Although a recent but small study suggests that AP is safe and well tolerated in pregnancy, additional data are needed. AP should not be given with other proguanil-containing medications, or with tetracycline, rifampin, rifabutin, and metoclopramide, which significantly reduce the plasma concentration of atovaquone.
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