Sudden Death in a Traveler Following Halofantrine Administration ---Togo, 2000

On July 17, 2000, a previously healthy 22-year-old U.S. student collapsed and died suddenly while leading a teenage exchange group in West Africa. This report summarizes the results of the investigations of this incident, which implicate use of halofantrine for treatment of malaria as the cause of death. Travelers should be warned that halofantrine treatment may be dangerous in persons with cardiac abnormalities or in those taking mefloquine for malaria prophylaxis.

The student began taking mefloquine for malaria prophylaxis approximately 1 week before departure on July 5. On July 12, he developed fever of 102 F (39 C), chills, headache, and cough, and was seen at a clinic in Togo 2 days later. He was diagnosed with malaria and bronchopneumonia and treated orally with halofantrine, dirithromycin, and acetylcysteine. The patient defervesced over the following 24 hours and resumed normal activities on July 13.

On July 14, following a 2-hour car ride, he stepped from the car, complained of a "head rush," and collapsed. Cardiopulmonary resuscitation was unsuccessful, and he was later pronounced dead at a local medical center. On July 24, an autopsy was performed at Yale-New Haven Medical Center, which revealed a previously undiagnosed atypical asymmetric hypertrophic cardiomyopathy.

Reported by: D Irons, MD, Tufts Univ School of Medicine, Boston, Massachusetts. J Morrow, MD, Yale Univ Medical Center, New Haven, Connecticut. Malaria Epidemiology Br, Div of Parasitic Diseases, National Center for Infectious Diseases; and an EIS Officer, CDC.

Editorial Note:

This report underscores precautions about halofantrine use for treating malaria, especially among travelers who are taking mefloquine prophylaxis. In the case of this traveler, who had been taking mefloquine for prophylaxis and had been in a malarious area for only 1 week, the diagnosis of malaria probably was erroneous. The patient in this report also received dirithromycin, a macrolide antibiotic that may have exacerbated the cardiac effects of mefloquine and halofantrine (1).

Halofantrine is a synthetic phenanthrene-methanol antimalarial and is chemically related to quinine and mefloquine. The drug has been approved for use in the United States and is marketed internationally but not in the United States. Although halofantrine is an efficacious treatment for Plasmodium falciparum malaria (2), the drug can cause rare but serious cardiac complications (3). The drug has been associated with lengthening of the QT interval in patients without known cardiac abnormalities (4--6) and with fatal or near-fatal arrhythmias in some persons (6,7). Although this patient had no family history of heart disease, hypertrophic cardiomyopathy, which has been associated with QT prolongation and an increased risk for sudden cardiac death (8), was discovered at autopsy.

QT prolongation may occur more frequently when halofantrine is administered following mefloquine (6), and prescribing information for halofantrine warns against its use in those taking mefloquine (9). The manufacturer and others also recommend that halofantrine be used for treatment only in persons who have a normal electrocardiogram, which makes its use in many less-developed settings impractical (4,9).

Travelers to remote areas should consider carrying antimalarials for presumptive self-treatment should they become ill with symptoms of malaria and are unable to obtain prompt medical care. Both sulfadoxine-pyrimethamine (Fansidar*, Roche Laboratories, Nutley, New Jersey), and atovaquone-proguanil (Malarone, Glaxo Wellcome, Research Triangle Park, North Carolina) are acceptable options for presumptive self-treatment, depending on local drug resistance patterns (10). However, all travelers should be cautioned that presumptive self-treatment for malaria is not a substitute for a prompt medical evaluation.

Halofantrine treatment may be dangerous in those with cardiac abnormalities or in those taking mefloquine for malaria prophylaxis. However, because P. falciparum malaria is a potentially life-threatening illness, the benefit of halofantrine treatment may outweigh the risks in the case of laboratory-confirmed P. falciparum infection if no other effective therapies are available. Additional information about malaria prophylaxis and treatment is available from CDC by telephone, (888) 232-3228, fax, (888) 232-3299, or on the World-Wide Web, http://www.cdc.gov/travel.

References

1. Drici MD, Knollmann BC, Wang W-X, Woosley RL. Cardiac actions of erythromycin: influence of female sex. JAMA 1998;280:1774--6.
2. ter Kuile FO, Dolan G, Nosten F, et al. Halofantrine versus mefloquine in treatment of multidrug-resistant falciparum malaria. Lancet 1993;341:1044--9.
3. Touze JE, Fourcade L, Peyron F, Heno P, Deharo JC. Is halofantrine still advisable in malaria attacks? Ann Trop Med Parasitol 1997;91:867--73.
4. Monlun E, LeMetayer P, Szwandt S, et al. Cardiac complications of halofantrine: a prospective study of 20 patients. Trans Roy Soc Trop Med Hyg 1995;89:430--3.
5. Touze JE, Bernard J, Keundjian A, et al. Electrocardiographic changes and halofantrine plasma level during acute falciparum malaria. Am J Trop Med Hyg 1996;54:225--8.
6. Nosten F, ter Kuile FO, Luxemburger C, et al. Cardiac effects of antimalarial treatment with halofantrine. Lancet 1993;341:1054--5.
7. Akhtar T, Imran M. Sudden deaths while on halofantrine treatment---a report of two cases from Peshawar. J Pak Med Assoc 1994;44:120--1.
8. Yetman AT, Hamilton RM, Benson LN, McCrindle BW. Long-term outcome and prognostic determinants in children with hypertrophic cardiomyopathy. J Am Coll Cardiol 1998;32:1943--50.
9. Prescribing information: Halfan^® brand of halofantrine hydrochloride tablets [package insert]. Philadelphia, Pennsylvania: SmithKline Beecham Pharmaceuticals, 1997.
10. CDC. Information for health care providers: Malarone for malaria treatment and prophylaxis. Available at http://www.cdc.gov/travel/diseases/malaria/malarone.htm. Accessed January 2001.

* Use of trade names is for identification only and does not imply endorsement by CDC or the U.S. Department of Health and Human Services.

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