Travel to Malaria-Endemic Areas Requires a Mosquito Map

CAMBRIDGE, Mass., Nov. 8 -- Malaria prophylaxis may require the individualized guidance of a tropical-disease specialist for those embarking on lengthy trips to disease-endemic countries.

Aiming at the likes of diplomats, students, missionaries, Peace Corps volunteers, military personnel, teachers, field researchers, and corporate employees, a tropical disease team here warned of counterfeit drugs on top of the quixotic nature of malaria.

"Long-term travelers underuse personal protective measures and adhere poorly to continuous chemoprophylaxis regimens," pointed out Lin H. Chen, M.D., of Mount Auburn Hospital here, and colleagues, in a review the Nov. 8 issue of the Journal of the American Medical Association.

"For long-term travelers visiting malaria-endemic countries, recommendations for prevention have been difficult to standardize due to the diversity of long-term travelers and their itineraries, the variation in quality of and access to medical care, the limited data on malaria incidence in travelers overseas, and the lack of controlled studies on long-term safety and efficacy of antimalarial agents," the authors wrote. "Further complicating the recommendations are the evolution in the intensity of transmission and resistance patterns of the malaria parasites, the seasonality of transmission, and the wide range of international guidelines and travelers' beliefs and expectations."

They cited a number of strategies used during long-term stays, such as discontinuation of chemoprophylaxis after the initial period, sequential regimens with different medications for chemoprophylaxis, stand-by emergency self-treatment, and seasonal chemoprophylaxis targeting high incidence periods or locations.

"All strategies have advantages and drawbacks," said the authors.

They noted that malaria risk varies widely by geographic region, with rates were highest in Africa and Oceania, intermediate in South Asia, and lower in Central and South America and Southeast Asia.

The researchers offered a general algorithm for advising long-term travelers, who have a higher risk of mosquito-transmitted malaria than those who travel for shorter periods.

"Any preparation should begin with education about basic elements of malaria transmission that will be tailored to the region where the person will be living and working," they wrote.

"Key messages include seriousness of the infection, protean manifestations of malaria, potential for rapid progression, need for rapid assessment and possible onset many months after exposure, especially with [Plasmodium vivax] malaria," they added.

Prospective travelers should also receive information about destination-specific habits and biting times of the mosquitoes and other local disease vectors along with how to recognize and treat malaria symptoms.

Travelers going to remote areas should be provided with medication for stand-by emergency treatment (SBET) and written guidelines on its use, Dr. Chen and colleagues said. The WHO defines it as "the use of antimalarial drugs carried by the traveler for self-administration when malaria is suspected and prompt medical attention is unavailable within 24 hours of onset of symptoms."

The CDC recommends Malarone (atovaquone-proguanil) as an ideal emergency treatment, as do many European countries, the researchers said. Aralen (chloroquine) was recommended only for use in Central America because of widespread resistance elsewhere. Lariam (mefloquine) is reasonably priced but "has been associated with considerable adverse events at therapeutic doses," they cautioned. Halfan (halofantrine) and Fansidar (sulfadoxine-pyrimethamine) are not recommended because of fatal adverse events.

"Because of the concern for resistance and additive toxicity, the medication used for [stand-by emergency treatment] should differ from what the traveler uses for chemoprophylaxis," the authors wrote.

Chemoprophylaxis regimens with various medications typically provide about 75% to 95% protection from malaria even if taken correctly. Based on a literature review, the researchers reported:

• Aralen or Plaquenil (hydroxychloroquine sulfate) has been used continuously for years by travelers but can cause retinal toxicity after five to six years of weekly dosing. After this point, ophthalmologic examination should occur every six to 12 months.
• Lariam is a conveniently dosed option for travelers to areas with Aralen-resistant malaria, and has wide experience and relatively good tolerability for prolonged use. However, serious adverse events have been a concern early in prophylaxis.
• Primaquine can only be used by travelers without glucose-6-phosphate dehydrogenase deficiency but has been reported to be well-tolerated for up to 52 weeks.
• Malarone appears to be safe for use for at least two years but post-marketing surveillance reported gastrointestinal and neuropsychiatric adverse events in 10% and 8.5% of users, respectively.
• Doxycycline has a licensed duration of only four months in the United States, but has been tested for use up to 12 months in Cambodia.

In considering preventive medication, clinicians should assess malaria risk for the traveler's specific destination, the investigators said. They suggested:

• Continuous chemoprophylaxis for high-risk areas.
• Continuous or possibly seasonal chemoprophylaxis for moderate- or limited-risk areas.
• For low risk areas, continuous chemoprophylaxis or consideration of seasonal chemoprophylaxis or even stand-by emergency treatment only.

Regardless of local conditions or malaria prevention strategies used, it is crucial for all travelers to identify reliable medical facilities at their destinations, the researchers cautioned. However, travelers should purchase antimalarial drugs at home or have them delivered from a reputable source since counterfeit drugs are rampant, they added.

Also, presumptive antirelapse treatment with primaquine should be considered for all travelers to areas with significant Plasmodium vivax transmission, Dr. Chen and colleagues suggested. Relapses of P. vivax malaria are not prevented with first-line chemoprophylaxis regimens.

While guidelines primarily address Plasmodium falciparum infections in short-term travelers, the recommendations on personal protective measures apply to longer stays as well, Dr. Chen and colleagues said. These measures include:

• Window and door screens.
• Insecticide-impregnated bed nets and clothing.
• Insect repellents (DEET, N,N-diethyl-m-toluamide or N,N-diethyl-3-methylbenzamide, has "the best evidence and longest history of use, and is considered the most reliable").
• Knockdown sprays to kill mosquitoes on contact.
• Insecticide coils.

Finally, said the authors, a recent report identified at least 12 different counterfeit artesunate products in circulation in Southeast Asia.

"Counterfeit drugs, including antimalarial drugs, are widely distributed, especially in Asia," they added. "Long-term travelers are likely to purchase their drugs in the country of temporary residence unless they return frequently to their home country or can arrange shipment or delivery of drugs. Problems with counterfeit drugs include incorrect amount of active ingredient, toxic or allergenic additions to medication, and formulations that may have different pharmacokinetic properties."

One of the authors reported financial disclosures for Roche and GlaxoSmithKline.