BACKGROUND: Chloroquine plus proguanil is widely used for malaria chemoprophylaxis despite low effectiveness in areas where multidrug-resistant malaria occurs. Studies have shown that atovaquone and proguanil hydrochloride is safe and effective for prevention of falciparum malaria in lifelong residents of malaria-endemic countries, but little is known about non-immune travellers.

METHODS: In a double-blind equivalence trial, 1083 participants travelling to a malaria-endemic area were randomly assigned to two treatment groups: atovaquone-proguanil plus placebos for chloroquine and proguanil, or chloroquine, proguanil, and placebo for atovaquone-proguanil. Follow-up was by telephone 7 and 60 days after travel and at a clinic at 28 days. Serum samples were tested for antibodies to a malaria circumsporozoite protein. Blood and serum samples of participants with a potential malaria diagnosis were tested in a reference laboratory.

FINDINGS: 7 days after travel, at least one adverse event was reported by 311 (61%) of 511 participants who received atovaquone-proguanil and 329 (64%) of 511 who received chloroquine-proguanil. People receiving atovaquone-proguanil had a lower frequency of treatment-related gastrointestinal adverse events (59 [12%] vs 100 [20%], p=0.001), and of treatment-related adverse events of moderate or severe intensity (37 [7%] vs 56 [11%], p=0.05). There were fewer treatment-related adverse events that caused prophylaxis to be discontinued in the atovaquone-proguanil group than in the chloroquine-proguanil group (one [0.2%] vs ten [2%], p=0.015).

INTERPRETATION: Overall the two preparations were similarly tolerated. However, significantly fewer adverse gastrointestinal events were observed in the atovaquone-proguanil group in than in the chloroquine-proguanil group.