Malarone for Chemoprophylaxis of Malaria
Malarone for Chemoprophylaxis of Malaria
Abstract & Commentary
Synopsis: Malarone, an oral antimalarial containing a fixed combination of atovaquone and proguanil (A/P), was released in August 2000 for the chemoprophylaxis and treatment of malaria. This drug had been studied extensively for prevention and treatment of Plasmodium falciparum malaria in semi-immune hosts (ie, persons who live in malaria-endemic regions and are assumed to be partially immune to malaria), but it had not been evaluated in nonimmune persons such as a traveling population.
Source: Hogh B, et al. Atovaquone-proguanil versus chloroquine-proguanil for malaria prophylaxis in non-immune travelers: A randomised, double-blind study. Lancet. 2000; 356:1888-1894.
Publication of the first trial of Malarone chemoprophylaxis in travelers was highly anticipated. Would the drug be well-tolerated in travelers and provide the same excellent protection that had been seen in semi-immune populations? In this trial, 21 travel clinics in Europe, Canada, and South Africa collaborated in a study of 1022 adolescents and adults traveling to malaria-endemic areas for up to 28 days. GlaxoSmithKline, the manufacturer of Malarone, funded the trial. Travelers were randomized to take either Malarone or chloroquine-proguanil (C/P). Because of different dosing schedules for the 2 regimens (Malarone 1 tablet daily, chloroquine 2 capsules weekly, and proguanil 2 capsules daily), travelers took additional placebo pills to allow a double-blind trial. Travelers were surveyed by telephone both 7 and 60 days following travel and seen at a clinic visit at 28 days. They were asked about their health during travel—which included questions about medication side effects and signs/symptoms of malaria. They were provided a diagnostic kit to use if malaria was suspected. The kit contained a card to record details about the diagnosis, slides for blood smears, and filter strips for PCR amplification of parasite DNA in a blood sample. Infection with Plasmodium falciparum was assessed using serum samples and testing for antibody to circumsporozoite protein (the repeat region of the P falciparum sporozoite) at baseline and 28 days. Some participants had hemograms and chemistries checked at 28 days. The primary study end point was the overall frequency of adverse events 7 days following departure from the malaria-endemic region. Secondary end points were the frequency of treatment-limiting adverse events and efficacy of prophylaxis.
A total of 1008 persons completed the trial—501 in the A/P group and 507 in the C/P group. Sixty-three percent traveled to countries in Africa. At 7 days, 22% of the A/P group reported treatment-related side effects compared with 28% of the C/P group (P = .024). When gastrointestinal side effects were compared, there were significantly more side effects in the C/P group (20% vs 12%; P = .001). This was not the case when neuropsychiatric side effects were examined (10% each group). Severe events, not delineated, were reported in 5 persons taking A/P and 11 persons on C/P. Eleven persons discontinued A/P because of adverse events and 16 discontinued C/P. For the 180 persons who had laboratory testing, there were no differences in the laboratory results between the groups, and no "clinically important" abnormalities were detected.
Clinical malaria was confirmed in 4 travelers; 3 cases of P falciparum occurred in persons while they were taking C/P, and 1 case of Plasmodium ovale occurred 28 days following completion of A/P. In the cases of P falciparum, parasites were resistant to chloroquine and had decreased sensitivity to proguanil by genetic testing. Antibody to the circumsporozoite protein was detected in 7 people taking A/P and 8 people taking C/P. The minimum protective efficacy of A/P for P falciparum was 100% (95% CI: 59-100%) and for C/P 70% (35-93%).
Comment by David R. Hill, MD, DTM&H
The fixed combination of A/P is highly effective for both the treatment1 and prophylaxis2 of P falciparum malaria in persons who live in areas endemic for malaria.3 In treatment studies, Malarone has been shown to be more effective than mefloquine for adults in Thailand,4 than amodiaquine in adolescents and adults in Gabon,5 and chloroquine or chloroquine plus sulfadoxine/pyrimethamine (Fansidar) in adolescents and adults in the Philippines.6 It was equally effective as Fansidar® for adolescents and adults in Zambia,7 as quinine and tetracycline in adults in Brazil,8 and as halofantrine in children in Kenya.9 In each of these trials, the efficacy of Malarone ranged from 87% to 100%. It also has activity in treatment of nonfalciparum malaria species13,14 but does not eradicate the hypnozoite form of Plasmodium vivax or P ovale. Therefore, primaquine phosphate is required for radical cure of these species.
In prophylaxis studies, it was highly effective (> 95% protection) in protecting against P falciparum in adults in Kenya10 and Zambia,11 and in children in Gabon.12
The trial by Hogh and colleagues of Malarone’s tolerance in nonimmune travelers is the necessary complement to studies in semi-immune persons. The drug was well-tolerated, and people experienced few side effects or treatment-limiting events. Although efficacy was not a primary end point, the diagnosis of malaria was rigorously examined and Malarone was highly effective. Nevertheless, the exposure of this group of travelers to malaria is not definitively known (there were only 15 persons who developed antibody to circumsporozoite protein, suggesting limited exposure). Malarone will need to be studied in additional groups with varying levels of exposure to malaria to gain a complete picture of efficacy. A study presented at the 40th Interscience Conference on Antimicrobial Agents and Chemotherapeutics in Toronto, Canada, last year included travelers on Malarone compared to those on mefloquine,15 and a small study of nonimmune South Africans taking Malarone for new exposure to malaria was published in 1999.16 In both of these groups, Malarone was highly effective.
The place of Malarone in malaria chemoprophylaxis and treatment will evolve as more experience is gained with the drug. Many travelers who are concerned about potential neuropsychiatric side effects of mefloquine will choose Malarone for prophylaxis. It has an advantage of having causal prophylactic efficacy against P falciparum (ie, killing developing erythrocytic phase organisms),17,18 and this permits the early discontinuation of the drug following exposure to P falciparum malaria. It is ideal for the traveler who will have short-term exposure to malaria, such as the traveler to South Africa who will be in Kruger National Park for only a few days during a trip. They can start the drug the day before exposure, take it during exposure, and for a week thereafter. It can be used as an alternative to doxycycline for prevention of multi-drug resistant P falciparum, which may be encountered by the rare traveler who visits rural, forested, border areas of Thailand with Cambodia and Myanmar,4 and by travelers who visit the ruins of Ankor Wat in Siam Reap, Cambodia. It is an option for self-treatment of malaria in the event of failure of chemoprophylaxis during travel. Finally, its availability in a pediatric formulation makes it convenient to prescribe malaria medication for children and provides an option for children younger than the age of 8 years who are intolerant of mefloquine, and in whom doxycycline is contraindicated. For long-term travelers with exposure to P vivax or P ovale, consideration should be given to terminal prophylaxis with primaquine, since Malarone will not eradicate the hypnozoite phase of these parasites. It currently is not recommended for use during pregnancy, since atovaquone is in pregnancy category C.
An important consideration is cost, which is now about $10 per pill, making its use problematic for use in long-term travelers.3 Francois Nosten raised the issue of cost and the place of Malarone in a global context in a thoughtful Lancet editorial that accompanied the Hogh paper.19 He asked if this drug would be available for treatment of malaria in the developing world’s population that suffers most from the burden of malaria? Will resistance develop if the drug is used indiscriminately? These are important issues to address by travel and tropical medicine specialists and by the drug’s manufacturer, GlaxoSmithKline.
For specific CDC recommendations on the use of Malarone, the CDC web site can be accessed at www.cdc.gov/travel/diseases/malaria/malarone.htm.
References
1. Looareesuwan S, et al, for the Malarone Clinical Trials Study Group. Malarone© (atovaquone and proguanil hydrochloride): A review of its clinical development for treatment of malaria. Am J Trop Med Hyg. 1999;60: 533-541.
2. Shanks GD, et al. Atovaquone and proguanil hydrochloride for prophylaxis of malaria. J Travel Med. 1999;6(suppl 1):S21-S27.
3. Medical Letter. Atovaquone/proguanil (Malarone©) for malaria. Med Lett Drug Ther. 2000;42:109-111.
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. Radloff PD, et al. Atovaquone and proguanil for Plasmodium falciparum malaria. Lancet. 1996;347: 1511-1514.
6. Bustos DG, et al. Atovaquone-proguanil compared with chloroquine and chloroquine-sulfadoxine-pyrimethamine for treatment of acute Plasmodium falciparum malaria in the Philippines. J Infect Dis. 1999; 179:1587-1590.
7. Mulenga M, et al. Atovaquone and proguanil versus pyrimethamine/sulfadoxine for the treatment of acute falciparum malaria in Zambia. Clin Ther. 1999;21: 841-852.
8. de Alencar PE, et al. Atovaquone and proguanil for the treatment of malaria in Brazil. J Infect Dis. 1997; 175:1544-1547.
9. Anabwani G, et al. Combination atovaquone and proguanil hydrochloride vs. halofantrine for treatment of acute Plasmodium falciparum malaria in children. Pediatr Infect Dis J. 1999;18:456-461.
10. Shanks GD, et al. Efficacy and safety of atovaquone/proguanil as suppressive prophylaxis for Plasmodium falciparum malaria. Clin Infect Dis. 1998;27:494-499.
11. 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.
12. Lell B, et al. Randomised placebo-controlled study of atovaquone plus proguanil for malaria prophylaxis in children. Lancet. 1998;351:709-713.
13. Radloff PD, et al. Atovaquone plus proguanil is an effective treatment for Plasmodium ovale and P malariae malaria. Trans R Soc Trop Med Hyg. 1996;90:682.
14. Looareesuwan S, et al. Atovaquone and proguanil hydrochloride followed by primaquine for treatment of Plasmodium vivax malaria in Thailand. Trans R Soc Trop Med Hyg. 1999;93:637-640.
15. Overbosch D, et al. Atovaquone/proguanil versus mefloquine (MFQ) or chloroquine/proguanil (C/P) in randomised, double-blind clinical trials of malaria prophylaxis in non-immune travelers (abstract). In: 40th Interscience Conference on Antimicrobial Agents and Chemotherapeutics. 2000. Toronto, Ontario: p. L-8.
16. 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.
17. Chulay JD. Challenges in the development of antimalarial drugs with causal prophylactic activity. Trans R Soc Trop Med Hyg. 1998;92:577-579.
18. Shapiro TA, et al. Prophylactic activity of atovaquone against Plasmodium falciparum in humans. Am J Trop Med Hyg. 1999;60:831-836.
19. Nosten F. Prophylactic effect of Malarone© against malaria: All good news? (editorial). Lancet. 2000; 356:1864-1865.
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