Long-Term Malaria Prophylaxis for Travelers

Jürgen Knobloch

Disclosures
In This Article

Drugs for Long-Term Use

WHO recommendations for chloroquine are generally accepted among physicians as the standard. The drug is appropriate for long-term use, and the risk of serious side effects associated with long-term prophylactic use is low.[3] Retinopathy associated with long-term use of chloroquine is a rare event, even if a cumulative chloroquine dose in excess of 300 g is used,[19] although it has been known to occur at lower doses.[20] Therefore, chloroquine requires screening for retinal changes once every 2 years when taken for more than 3 (700 mg/wk) or 5 (300 mg/wk) years. With increasing drug resistance, however, indications for such chemoprophylaxis are decreasing. In Germany, for example, chemoprophylaxis is no longer recommended for travelers going to any endemic area, with or without proguanil (which is usually combined with chloroquine). Using daily proguanil in addition to chloroquine has not always been shown to provide additional protection.[21]

Because of increasing drug resistance in the past 15 years, chloroquine and proguanil have been gradually replaced by mefloquine for both short- and long-term prophylaxis.[22] Major studies of mefloquine tolerability, as well as worldwide monitoring, have shown that serious adverse events are rare,[23] and it is usually safe and well tolerated for long-term prophylaxis, particularly in males.[3,22,24,25] There is no measurable accumulation of mefloquine in the serum,[15,16,26] even when every-other-week dosing is replaced by weekly dosing, the latter which is more effective as shown in the 1990s.[25,27] Mefloquine-resistant parasites, however, have been isolated from military, long-term travelers since the early 1990s.[25] Female travelers should be informed of an increased risk of neuropsychiatric side effects during long-term prophylaxis. Mefloquine plasma levels do not show substantial gender-specific differences[28]; thus, recommendations on dose reduction for female travelers under long-term mefloquine prophylaxis so far lack scientific support.

Both mefloquine and doxycycline are appropriate prophylactic drugs for chloroquine-resistant infections, which now occur in nearly all of the Plasmodium falciparum -endemic areas. There is little information regarding long-term (> 6 mo) use of doxycycline; however, available data are reassuring.[29] There is considerable information regarding its use in long-term therapy for acne, Q fever endocarditis,[30] and small, asymptomatic, abdominal aortic aneurysms.[31] As for malaria chemoprophylaxis, the drug has predominantly been tested by military personnel, and the incidence of adverse events as well as the effectiveness were acceptable.[29,32] The major side effects are episodes of cutaneous photosensitivity reactions, tooth discoloration, yeast infection, and gastrointestinal symptoms,[31] including esophageal perforation. National regulations, such as those regarding the patient's formal or informal consent, should be considered when the drug is not specifically licensed for malaria prophylaxis. There is no general limitation or restriction for the use of doxycycline in the CDC recommendations.[2] The monohydrate formula of doxycycline is better tolerated than the hyclate formula.[33]

In some countries (not the United States), the use of atovaquone-proguanil is restricted to 28 days plus 1 to 2 days before and 1 week after the stay in the endemic area. However, in single observations as well as in clinical studies, the drug has proved to be appropriate for long-term prophylaxis. For example, in Indonesia over a 20-week duration, the daily dose of 250 mg atovaquone plus 100 mg proguanil (1 adult tablet of Malarone) prevented most of the 148 transmigrants from contracting vivax or falciparum malaria with a protective efficacy of 84 and 96%, respectively.[34] A 6-month safety study in Danish soldiers showed that the drug was well tolerated and effective.[35] A recent postmarketing surveillance showed atovaquone-proguanil to be well tolerated by long-term travelers taking the drug for up to 34 weeks.[36] Since the drug is considered causal prophylaxis, that is, acting on the plasmodial liver stage, it may be discontinued after 1 week, as compared with 4 weeks after departure from the malarious area in the case of mefloquine. It is particularly useful for a subset of long-term travelers, namely, those who travel frequently to and from endemic areas, to provide them some relief from continuous drug consumption. Atovaquone-proguanil has been well accepted by the travel community because of its lower rate of severe and neuropsychiatric side effects compared with mefloquine.[37]

Primaquine is used for relapse prevention against vivax and ovale malaria. It is also effective for causal chemoprophylaxis. In order not to risk severe hemolysis, those with glucose-6-phosphate dehydrogenase deficiency should be excluded. Recently, Javanese transmigrants were protected against falciparum and vivax malaria at an efficacy of 93% when they took daily doses of 30 mg for 20 weeks.[38] An earlier study in Javanese men showed primaquine to be 94.5% effective for prevention of Plasmodium falciparum infection and 90.4% for Plasmodium vivax infection when used for 1 year.[39] In both studies the drug was well tolerated. Primaquine is usually not licensed for long-term malaria chemoprophylaxis. The CDC recently added it to their list of approved drugs but did not stipulate whether it should be used for short or long terms.[2]

In clinical phase 2 studies, another 8-aminoquinoline, tafenoquine, has been shown to be effective in 86 or 89% when given in 200 or 400 mg weekly doses, respectively, for up to 13 weeks in Kenya.[40] Apparently, the drug will not be released for marketing in the near future.

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