Atovaquone-proguanil versus chloroquine-proguanil for malaria prophylaxis in non-immune travellers: a randomised, double-blind study

Summary

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 gastro-intestinal events were observed in the atovaquone-proguanil group in than in the chloroquine-proguanil group.

Introduction

Malaria is one of the greatest threats to health for international travellers. The number of reported cases of malaria in Europe increased from 6840 in 1985, to 8438 in 1995, with a case-fatality rate as high as 3·6%.¹ Imported malaria is also a problem in North America, with more than 1000 cases reported annually in the USA and Canada.2, 3

Imported malaria mainly occurs when travellers fail to use appropriate chemoprophylaxis or do not use it correctly.³ Widespread parasite resistance renders chloroquine poorly effective in most malaria-endemic countries.⁴ Mefloquine is highly effective in preventing malaria but has been associated with neuropsychiatric side-effects that may be severe and can restrict its use.⁵ The combination of chloroquine plus proguanil has fewer serious side-effects than mefloquine⁶ and is more effective than chloroquine alone, but still less effective than mefloquine.⁷ An additional drawback with drugs widely used for malaria prophylaxis is that they must be continued for 4 weeks after leaving a malaria-endemic area.⁸ There is a clear need for better drugs to prevent malaria.

In controlled clinical trials with more than 600 participants, a fixed-dose combination of atovaquone and proguanil hydrochloride was 98% effective in prophylaxis of malaria caused by Plasmodium falciparum and had a safety profile similar to that of placebo.9, 10, 11, 12 However, these studies were done on lifelong residents of malaria-endemic countries, who may have had some immunity to malaria. Additionally, the frequency and nature of adverse events might differ between travellers and residents of endemic areas. We have undertaken a randomised, double-blind trial to compare the safety and efficacy of atovaquone-proguanil versus chloroquine-proguanil in non-immune travellers. The hypothesis was that the frequency of adverse events in participants receiving atovaquone-proguanil was not higher than in those receiving chloroquine-proguanil. The frequency of treatment-limiting adverse events and efficacy of prophylaxis were secondary endpoints.