Update on Malaria Prophylaxis and Treatment from the ASTMH Meeting
Update on Malaria Prophylaxis and Treatment from the ASTMH Meeting
CONFERENCE COVERAGE
By David R. Hill, MD, DTM&H
The annual update on malaria prophylaxis was held during the meeting of the American Committee on Clinical Tropical Medicine and Traveler’s Health. There were three speakers: Dr. Monica Parise of the Centers for Disease Control and Prevention, Dr. Jeff Chulay of Glaxo Wellcome, and Dr. Hans Nothdurft of the University of Munich. Parise detailed the few changes to the malaria section on the soon-to-be-released CDC publication, Health Information for International Travel 1998, and reviewed other CDC recommendations, Chulay described the new antimalarial, malarone, and Nothdurft discussed malaria prevention from the perspective of European travel medicine physicians.
Epidemiology
Plasmodium vivax malaria has re-emerged in South Korea on the Western edge of the Demilitarized Zone, north of the Imjin River. After a 15-year absence of malaria in South Korea, there has been a steady increase in cases originating from this area since 1993 (1 case in 1993, 22 in 1994, 107 in 1995, and 356 in 1996). According to the most recent statistics for 1997, there had been 1145 cases in the Korean military, 27 in the U.S. military, and 381 in Korean civilians. Nearly half of the cases have had a clinical incubation period of 6-9 months. The Korean military has initiated chloroquine prophylaxis for the highest period of risk from June to September. The U.S. military has not instituted prophylaxis as of yet. In spite of this re-emergence, chemoprophylaxis is not recommended for U.S. tourists, since travel to this area is restricted and occurs during daytime hours.
Chemoprophylaxis
A loading dose for mefloquine is not recommended by the CDC. Some travel medicine physicians give a loading dose (250 mg of mefloquine daily for 3 days, then weekly) to rapidly achieve therapeutic levels and to try to "screen" for side effects before the traveler departs. Although this appears to be safe and generally well-tolerated, there has been no documentation of cases of malaria related to not giving a loading dose. There is also concern that such a regimen will lead to confusion on the part of the traveler and the potential for misuse of the drug.
Updated information on neuropsychiatric mefloquine side effects from Hoffman LaRoche based on approximately 50,000 users was presented by Nothdurft. Severe effects requiring hospitalization occurred in 0.01% of users, serious side effects requiring discontinuation of the drug occurred in 2%, mild-to-moderate symptoms such as dizziness and weird dreams in 10%, and any side effects in 17%. These incidence rates seem to be in line with existing data that indicate severe effects in 1/13,000 users1 and events requiring stopping the drug in 7/1000.2
Malarone is a new product produced by Glaxo Wellcome that combines a fixed combination of atovaquone (250 mg) with proguanil (100 mg) for the prophylaxis and treatment of malaria.3 Atovaquone has been used extensively for treatment of Pneumocystis carinii pneumonia in AIDS patients; proguanil has been used for many years as part of a two-drug regimen (with chloroquine) for prophylaxis of malaria. The mechanism of action of atovaquone is probably the inhibition of parasite mitochondrial electron transport; proguanil is a dihydrofolate reductase inhibitor. In combination, the drugs are synergistic.
When used as prophylaxis in trials in Kenya, the Zambia, South Africa, and Gabon, malarone had an overall prophylactic efficacy of 98%. There is also some evidence, particularly in challenge studies, that it will act as a causal prophylactic (i.e., treating early, exoerythrocytic stage parasites). If that proves to be accurate, it certainly could simplify malaria chemoprophylaxis by allowing travelers to discontinue the drug soon after leaving the malarious area. Malarone will be submitted for FDA review in the Spring of 1998.
One strategy being adopted by some European travel medicine specialists is not to give prophylaxis to selected travelers. The options for these travelers in the event of a febrile illness that could be malaria are to seek care overseas or to administer self-treatment. This emphasizes the importance of determining the itinerary of a traveler, the type of exposure they will have, and their ability to access medical care or to take self-treatment medication. A problem of self-treatment is highlighted by data indicating that less than 5% of patients ever take emergency, stand-by treatment, and of those who take it, only 10% actually have malaria. Thus, there needs to be improved self-diagnosis detection kits for travelers who elect this option.
For whom should no prophylaxis be considered? Nothdurft suggests that it should be travelers to areas with a low incidence of malaria or to areas that have exclusively vivax or ovale malaria. Also, short-term travelers, such as those going overnight for business or airline pilots, could consider not taking prophylaxis. Certainly, the medical expertise, confidence of the traveler, and access to medical care or self-treatment will need to be explored before this option is exercised. Patient education on strict mosquito avoidance will need to be emphasized.
Treatment
Halofantrine (Halfan, SmithKline Beecham) will be released to the U.S. market in 1998.4 It is approved for the treatment of mild-to-moderate infection with P. falciparum and P. vivax. It has demonstrated excellent efficacy in trials, although there has been cross resistance with mefloquine. It received FDA licensure in 1992 but never was released because of its cardiac side effect profile. Because of this problem, it will not be actively marketed; however, it will be available to the military and through wholesalers.
Halofantrine prolongs the QTc interval and has caused rare fatalities, especially in individuals with congenital prolongation of the QTc. Its effect is particularly marked after previous mefloquine use. Release of the drug comes with several caveats. Use will require a pre-treatment ECG and cardiac monitoring for 8-12 hours after administration. It also cannot be used in individuals with a QTc interval greater than 0.44 msec, a family history of prolonged QTc, a history of ventricular arrhythmia or unexplained syncope, or previous mefloquine use.
These restrictions make it unlikely that it will see wide use, and the CDC will recommend against using it for treatment. This is based on its adverse effects profile and the availability of safer alternatives. Thus, it is essentially precluded as standby self-treatment in the field. This is particularly so because many travelers will have been on mefloquine for prophylaxis, and if they develop malaria while on mefloquine, the parasite is likely to be cross-resistant to halofantrine. Travelers should be warned about being given halofantrine by indigenous health care providers.
The artemesinin derivatives have shown excellent activity for the treatment of resistant falciparum malaria. They are rapidly active and effective against early stage parasites, but there is recrudescence of malaria. Thus, these agents are best combined with other drugs such as mefloquine or quinine. A concern with the artemesinins has been neurotoxicity.5 This has been seen in a dose-dependent fashion in dogs, rats, and rhesus monkeys. Nevertheless, it has been given to more than 1 million patients, primarily in Asia, with good results. Recently, there was a suggestion of delayed recovery from coma and increased convulsions in patients given artemesinin,6 but the true incidence and long-term sequelae are still not known. In the United States, there is interest in an Investigational New Drug protocol for the parenteral or rectal use of artemesinins in resistant cases of malaria.
Malarone has demonstrated more than 95% efficacy in studies in Thailand for the treatment of P. falciparum malaria, including chloroquine-resistant parasites. These results have been confirmed in additional trials in Thailand, Gabon, the Philippines, and Peru. When atovaquone is used alone, it is often effective, but there is unacceptable recrudescence and development of resistance. Malarone has already been approved for treatment of uncomplicated malaria in some European countries.
Chloroquine-resistant P. vivax has been a problem in some areas of Asia. For patients with this, treatment with chloroquine plus high-dose primaquine, mefloquine, halofantrine, or quinine ± doxycycline has been effective.
The availability of quinidine in hospitals has been a recent concern as quinidine is being used less frequently for the treatment of cardiac arrhythmias. The CDC is monitoring this and will attempt to assure its availability, perhaps through State Health Departments, if it becomes in short supply.
Finally, two recent publications concerning malaria are recommended. The first paper details the epidemiology of U.S. malaria, highlighting patterns, use of chemoprophylaxis, and factors contributing to fatal cases of malaria.7 The second is a review of the current state of prophylaxis for U.S. travelers.8
References
1. Weinke T, et al. Neuropsychiatric side effects after the use of mefloquine. Am J Trop Med Hyg 1991;45:86-91.
2. Barrett PJ, et al. Comparison of adverse events associated with use of mefloquine and combination of chloroquine and proguanil as antimalarial prophylaxis: Postal and telephone survey of travellers. BMJ 1996;313:525-528.
3. Mileno MD, Bia FJ. Malarone: Atovaquone and proguanil for treatment and prevention of malaria. TMA Update 1997;7:3-6.
4. Hill DR. Cardiac effects of halofantrine. TMA Update 1996;6:39-41.
5. Mileno MD. Artemisin derivatives: First-line antimalarial agents? TMA Update 1997;7:21-23.
6. van Hensbroek MD, et al. A trial of artemether or quinine in children with cerebral malaria. N Engl J Med 1996;335:69-75.
7. Kachur SP, et al. Malaria surveillanceUnited States, 1994. MMWR Morb Mortal Wkly Rep 1997;46 (SS-5): 1-18.
8. Lobel HO, Kozarsky PE. Update on prevention of malaria for travelers. JAMA 1997;278:1767-1771.
In recent years, Plasmodium vivax malaria has recurred in which country?
a. Russia
b. South Korea
c. Taiwan
d. Australia
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