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Abstract & Commentary
Synopsis: Malaria prophylaxis with Malarone (atovaquone plus proguanil) was effective and well tolerated in nonimmune travelers.
Source: Hogh B, et al. Atovaquone-proguanil versus chloroquine-proguanil for malaria prophylaxis in non-immune travellers: A randomised, double-blind study. Lancet. 2000;356: 1888-1894.
Hogh and colleagues, in a double-blind, placebo-controlled trial, randomised 1083 individuals travelling to a malaria-endemic area to receive prophylaxis with either daily atovaquone-proguanil (MalaroneÔ; 250 mg atovaquone plus 100 mg proguanil hydrochloride) or weekly chloroquine phosphate (500 mg) plus daily proguanil hydrochloride (PaludrineÔ, 100 mg), each together with appropriate placebos. Malarone was administered beginning 1-2 days prior to travel, during travel, and for 7 days after. Chloroquine was started 7 days before travel, while proguanil was started 1-2 days before; both were continued for 28 days after completion of travel.
Patients 14 years of age and older weighing at least 50 kg were enrolled at 21 travel clinics in northern Europe, the United Kingdom, Canada, and South Africa. The study was powered only to detect equivalence; 1008 completed the trial.
Compliance during pretravel, travel, and post-travel periods was, respectively, 95%, 96%, and 93% for Malarone; 94%, 91%, and 80% for chloroquine; and 90%, 94%, and 87% for proguanil. Thus, compliance (at least 80% of prescribed doses) during the post-travel period was significantly greater for Malarone than for either chloroquine (P = .001) or proguanil (P = .003).
Adverse events (excluding those occurring while individuals were receiving only placebo) were reported in 58% of Malarone recipients and in 64% of those given chloroquine-proguanil. Treatment-related adverse events, as determined by site investigators, occurred, respectively, in 22% and 28% (P = .024), with the difference mostly the result of more frequent gastrointestinal side effects among patients given chloroquine-proguanil. Moderate-to-severe adverse events were also more frequent in the latter group—11% vs. 7% in Malarone recipients (P = .05).
A diagnosis of Plasmodium falciparum malaria was made in 3 chloroquine-proguanil recipients; 1 probable case of P ovale infection occurred 28 days after completion of Malarone prophylaxis. Each of the 3 P falciparum isolates were found to have the K76T mutation in the pfcrt gene associated with chloroquine resistance, the S108N mutation in dhfr associated with pyrimethamine resistance as well as increased resistance to cycloguanil, and N51I and C59R mutations also associated with pyrimethamine resistance (high level). One isolate also contained a mutation N86Y) in pfmdr1.
Seven Malarone recipients and 8 chloroquine-proguanil recipients (including only 1 of the 3 with clinical malaria) developed antibody to P falciparum circumsporozoite antigens. Considering the number of individuals who developed antibody and/or clinical malaria as having been at high risk for malaria and using this number as the denominator, the minimal efficacy of Malarone was calculated to be 100% (95% confidence interval [CI], 59-100%) while that of chloroquine-proguanil was 70% (95% CI, 35-93%).
Comment by Stan Deresinski, MD, FACP
Atovaquone is a hydroxynapthoquinone that inhibits electron transport and alters mitochondrial membrane potential; proguanil enhances the ability of atovaquone to cause a collapse of that potential.1 Thus, the dominant activity of proguanil in this combination is as a biguanide, rather than via its DHFR-inhibiting metabolite, cycloguanil. P falciparum resistant to cycloguanil by virtue of mutations in DHFR do not exhibit reduced susceptibility to Malarone.2
While either component of Malarone given alone is poorly effective in the treatment of P falciparum malaria, the combination, which is synergistic in vitro, has potent blood schizonticidal activity and has been associated with an overall efficacy rate in excess of 98%. Therapy with Malarone has been demonstrated, in comparative trials, to be superior to mefloquine in Thailand, to amodiaquine in Gabon, and to chloroquine plus pyrimethamine/sufladoxine in the Philippines. The combination has been effective in all geographic areas in which it has been subject to examination and has been effective in generally nonimmune, as well as semi-immune, populations and has also been effective in the treatment of multiresistant malaria.3-5 Malarone is also effective in the treatment of P vivax infection, when followed by primaquine administration.6
In addition, studies in semi-immune populations have demonstrated that Malarone administration is effective as antimalaria prophylaxis. For instance, adults in an area of Zambia highly endemic for P falciparum malaria were initially treated with a curative therapeutic regimen of Malarone to eradicate existing infection due to this protozoan.7 They were then randomized to receive either placebo or Malarone daily for at least 10 weeks. Forty-one (37%) of 111 placebo recipients, but only 2 (2%) of 102 A/P recipients developed parasitemia (P < .001). While adverse effects overall were more commonly reported by placebo recipients, headache occurred approximately twice as frequently (9% vs 4%) in the A/P recipients. The efficacy rate of A/P prophylaxis in a semi-immune population in Kenya was 100% compared to a rate of only 48% (P < .001) for placebo recipients.8 Semi-immune African children living in a hyperendemic area were randomized, after initial curative therapy with A/P, to receive either placebo or Malarone for prophylaxis. Twenty-five (18%) of 140 children in the placebo group and none of the 125 children in the A/P group had detectable parasitemia during chemoprophylaxis (P < .001).9
Prophylactic efficacy in semi-immune populations does not, however, predict similar efficacy in non-immunes, such as travelers from nonendemic regions. Until now, there previously had been only very limited published data indicating efficacy in non-immune populations. This trial by Hogh et al is, therefore, the first large-scale randomized trial to fully demonstrate its efficacy and safety in such a population.10 The case of P ovale infection in a Malarone recipient is, however, indicative that this product, like mefloquine and chloroquine, lacks activity against hypnozoites. As a consequence, follow-up primaquine administration should be considered for travellers who have had unusually prolonged and/or intense potential exposure to P vivax or P ovale.
1. Srivastava IK, Vaidya AB. A mechanism for the synergistic antimalarial action of atovaquone and proguanil. Antimicrob Agents Chemother. 1999;43: 1334-1339.
2. Edstein MD, Yeo AE, Kyle DE. Proguanil polymorphism does not affect the antimalarial activity of proguanil combined with atovaquone in vitro. Trans R Soc Trop Med Hyg. 1996;90:418-421.
3. Blanchard TJ, et al. Multiresistant falciparum malaria cured using atovaquone and proguanil. Trans R Soc Trop Med Hyg. 1994;88:693.
4. Looareesuwan S, et al. Efficacy and safety of atovaquone/proguanil compared with mefloquine for treatment of acute Plasmodium falciparum malaria in Thailand. Am J Trop Med Hyg. 1999;60:526-532.
5. Looareesuwan S, et al. Malarone (atovaquone and proguanil hydrochloride): A review of its clinical development for the treatment of malaria. Am J Trop Med Hyg. 1999;60:533-541.
6. Sukwa TY, et al. A randomized, double-blind, placebo-controlled field trial to determine the efficacy and safety of Malarone (atovaquone/proguanil) for the prophylaxis of malaria in Zambia. Am J Trop Med Hyg. 1999; 60:521-525.
7. Shanks GD, et al. Efficacy and safety of atovaquone/ proguanil as suppressive prophylaxis for Plasmodium falciparum malaria. Clin Infect Dis. 1998;27:494-499.
8. Lell B, et al. Randomised placebo-controlled study of atovaquone plus proguanil for malaria prophylaxis in children. Lancet. 1998;351:709-713.
9. van der Berg JD, et al. Safety and efficacy of atovaquone and proguanil hydrochloride for the prophylaxis of Plasmodium falciparum malaria in South Africa. Clin Ther. 1999;21:741-749.