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QUESTION: In travellers who are not immune to malaria, is malaria prophylaxis with atovaquone proguanil equivalent to that with chloroquine proguanil for adverse events (AEs)?
Design
Randomised (allocation concealed*), blinded (clinicians and patients),* placebo controlled trial with follow up at 7, 28, and 60 days after leaving a malaria endemic area.
Setting
21 travel clinics in Denmark, the UK, France, Germany, the Netherlands, South Africa, and Canada.
Participants
1083 participants (mean age 36 y, 52% men, 96% white) who weighed >50 kg, were age ≥14 years, were in good health, and planned to travel ≤28 days in Africa (63%) or other Plasmodium falciparum endemic areas. Exclusion criteria included a history of seizures; psychiatric or neurological disorders; cardiac, hepatic, or renal dysfunction; pregnancy; alcoholism; malaria within the previous 12 months; or travel to a malaria endemic area within the previous 60 days. Follow up was 94% at 7 days and 93% at 60 days.
Intervention
540 participants were allocated to atovaquone, 250 mg/day, and proguanil hydrochloride, 100 mg/day, from 1 to 2 days before to 7 days after travel (and placebos for chloroquine proguanil). 543 participants were allocated to chloroquine, 310 mg/week, from 7 days before to 28 days after travel, and proguanil, 200 mg/day, from 1 to 2 days before to 28 days after travel (and placebos for atovaquone proguanil).
Main outcome measure
Number of AEs 7 days after return from a malaria endemic area.
Main results
Analysis was by intention to treat. Fewer drug attributed AEs (nausea, abdominal pain, and vomiting) and treatment limiting events occurred in the group receiving atovaquone-proguanil than in the group receiving chloroquine-proguanil (table). At 60 days, no participants in the atovaquone-proguanil group and 3 in the chloroquine-proguanil group had confirmed P falciparum malaria (p=0.08).
Atovaquone-proguanil v chloroquine-proguanil for drug attributed gastrointestinal (GI) adverse events and treatment limiting events in participants not immune to malaria†
Conclusion
Atovaquone-proguanil caused fewer gastrointestinal adverse events than chloroquine-proguanil in travellers who were not immune to malaria.
Commentary
The study by Høgh et al addresses the tolerability of 2 malaria drug prophylaxis regimens. Balancing the risks for developing malaria against the AEs of the drug prophylaxis makes the choice of drug difficult for many travellers to malaria endemic areas. The underlying problem in malaria drug prophylaxis is in the public perception of risk.1–3 Because travellers want to avoid AEs, the antimalarial drugs that cause fewer AEs will be used more frequently. The atovaquone-proguanil combination is effective in treating drug resistant malaria; however, it is too expensive to be used by many people in the developing countries in which it was tested.4 Nevertheless, it can still be useful to travellers, which is what the trial by Høgh et al evaluates.
It is not easy to show comparative benefits of 1 prophylactic regimen over another when AEs are few, but it seems unlikely that people will benefit from a regimen if they discontinue the drug while still exposed to the risk for infection. The trial by Høgh et al is instructive because it shows that the drug recommended for many years, chloroquine, can cause prophylaxis limiting events. The results are important for travellers because they show higher adherence with proguanil and atovaquone, a regimen effective against drug resistant malaria. The findings provide evidence to support a new drug option for preventing malarial infection in travellers.
Footnotes
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Sources of funding: Ontario Ministry of Health; PSI; Glaxo Wellcome.
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For correspondence: Malarone Publication Coordinator, Room 50-3505B, Glaxo Wellcome Inc, 5 Moore Drive, Research Triangle Park, NC 27709, USA. Fax +1 919 315 0377.