Drugs for preventing malaria in travellers
Abstract
Background
Malaria infects 10,000 to 30,000 international travellers each year. It can be prevented through anti‐mosquito measures and drug prophylaxis. However, antimalaria drugs have adverse effects which are sometimes serious.
Objectives
To compare the effects of currently used antimalaria drugs when given as prophylaxis to non‐immune adult and child travellers who are travelling to regions with Plasmodium falciparum resistance to chloroquine. Specifically, to assess the efficacy, safety, and tolerability of atovaquone‐proguanil, doxycycline, and mefloquine compared to each other, and also when compared to chloroquine‐proguanil and to primaquine.
Search methods
In August 2009 we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2008, Issue 4), MEDLINE, EMBASE, LILACS, BIOSIS, mRCT, and reference lists. We handsearched conference proceedings and one specialist journal, and contacted researchers and drug companies. We searched PubMed for drug‐related deaths.
Selection criteria
Randomized and quasi‐randomized controlled trials of any antimalaria drug regimen currently used by non‐immune international travellers.
Data collection and analysis
We independently extracted data and assessed eligibility and risk of bias using a standardized data collection form. We resolved any disagreement through discussion. We combined dichotomous outcomes using risk ratio (RR) and continuous data using mean difference (MD), presenting both with 95% confidence intervals (CI).
Main results
Eight trials (4240 participants) met the inclusion criteria. Evidence on comparative efficacy from head‐to‐head comparisons was limited. Atovaquone‐proguanil compared to doxycycline had similar adverse events reported. Compared to mefloquine, atovaquone‐proguanil users had fewer reports of any adverse effect (RR 0.72, 95% CI 0.6 to 0.85), gastrointestinal adverse effects (RR 0.54, 95% CI 0.42 to 0.7), neuropsychiatric adverse events (RR 0.86, 95% CI 0.75 to 0.99), and neuropsychiatric adverse effects (RR 0.49, 95% CI 0.38 to 0.63), besides a better total mood disturbance score (MD ‐7.20, 95% CI ‐10.79 to ‐3.61). Similarly, doxycycline users had fewer reported neuropsychiatric events than mefloquine users (RR 0.84, 95% CI 0.73 to 0.96). We also examined these three regimens against chloroquine‐proguanil; this latter regimen had more reports of any adverse effect (RR 0.84, 95% CI 0.73 to 0.96) and of gastrointestinal adverse effects (RR 0.71, 95% CI 0.6 to 0.85).
Authors' conclusions
Atovaquone‐proguanil and doxycycline are the best tolerated regimens, and mefloquine is associated with adverse neuropsychiatric outcomes.
PICOs
Plain language summary
Drugs for preventing malaria in travellers
Malaria is a mosquito‐transmitted disease which commonly infects international travellers, sometimes fatally. Deaths from malaria are usually caused by Plasmodium falciparum.
Malaria can be prevented through a range of anti‐mosquito precautions (barrier measures), and by taking antimalaria drugs (chemoprophylaxis). Chloroquine is effective chemoprophylaxis in those parts of the world where P. falciparum has not developed resistance to chloroquine. For most malaria‐endemic regions, however, travellers must take a newer and stronger drug regimen. These newer antimalaria regimens have unpredictable adverse effects, including severe illness or death.
This review was designed to assess the efficacy, safety, and tolerability of atovaquone‐proguanil, doxycycline, and mefloquine (the three currently available chemoprophylaxis choices for regions with P. falciparum resistance) compared to each other, and also when compared to chloroquine‐proguanil (an older drug combination) and to primaquine (a candidate for chemoprophylaxis).
We found eight trials (4240 participants). Overall the evidence base was small, and we found no evidence to support the use of primaquine. There was only limited evidence on which of the three currently available drugs is most effective in preventing malaria. While none of the eight trials reported any serious adverse events (which are usually rare) all trials reported common adverse events from antimalaria drugs.
Atovaquone‐proguanil and doxycycline are well tolerated by most travellers, and they are less likely than mefloquine to cause neuropsychiatric adverse events. Chloroquine‐proguanil causes more gastrointestinal adverse events than other chemoprophylaxis. In other respects, the common unwanted effects of currently available drugs are similar.
As well as the eight trials, we also found 22 published case reports of deaths, including five suicides, associated with mefloquine use at normal dosages. No other currently used drugs were reported as causing death, at normal dosages.
In conclusion, there were differences in the common unwanted effects of the drugs which are currently available to prevent malaria, in adult and child travellers. However, the quality of evidence was overall low. Atovaquone‐proguanil and doxycycline are the best tolerated regimens. Mefloquine has more adverse effects than other drugs, and these adverse effects are sometimes serious. However mefloquine may still be an appropriate choice for those travellers who have taken it previously, without any adverse events. Other factors should be considered by prescribers, in addition to tolerability: cost, ease of administration, possible drug‐drug interactions, travel itinerary, and the additional protection that may be afforded by doxycycline against other infections, besides malaria.
