• 1

    Thanh NV, Cowman AF, Hipgrave D, Kim TB, Phuc BQ, Cong LD, Biggs BA, 2001. Assessment of susceptibility of Plasmodium falciparum to chloroquine, quinine, mefloquine, sulfa-doxine-pyrimethamine and artemisinin in southern Vietnam. Trans R Soc Trop Med Hyg 95 :513–517.

    • Search Google Scholar
    • Export Citation
  • 2

    Taylor WR, Doan HN, Nguyen DT, Tran TU, Fryauff DJ, Gómez-Saladín E, Kain KC, Le DC, Baird JK, 2000. Assessing drug sensitivity of Plasmodium vivax to halofantrine or chloroquine in southern, central Vietnam using an extended 28-day in vivo test and polymerase chain reaction genotyping. Am J Trop Med Hyg 62 :693–697.

    • Search Google Scholar
    • Export Citation
  • 3

    Kimura M, Kaneko O, Liu Q, Zhou M, Kawamoto F, Wataya Y, Otani S, Yamaguchi Y, Tanabe K, 1997. Identification of the four species of human malaria parasites by nested PCR that targets variant sequences in the small subunit rRNA gene. Parasitol Int 46 :91–95.

    • Search Google Scholar
    • Export Citation
  • 4

    Milton KA, Edwards G, Ward SA, Orme ML, Breckenridge AM, 1989. Pharmacokinetics of halofantrine in man: effects of food and dose size. Br J Clin Pharmacol 28 :71–77.

    • Search Google Scholar
    • Export Citation
  • 5

    Basco LK, Le Bras J, 1992. In vitro activity of halofantrine and its relationship to other standard antimalarial drugs against African isolates and clones of Plasmodium falciparum.Am J Trop Med Hyg 47 :521–527.

    • Search Google Scholar
    • Export Citation
  • 6

    ter Kuile FO, Dolan G, Nosten F, Edstein MD, Luxemburger C, Phaipun L, Chongsuphajaisiddhi T, Webster HK, White NJ, 1993. Halofantrine versus mefloquine in treatment of multidrug-resistant falciparum malaria. Lancet 341 :1044–1049.

    • Search Google Scholar
    • Export Citation
  • 7

    World Health Organization, 2002. Monitoring Antimalarial Drug Resistance. Consultation, 2001. December 3–5, 2001. Geneva: World Health Organization, WHO/CDS/CSR/EPH/2002.17.

  • 8

    Sowunmi A, Falade CO, Oduola AM, Ogundahunsi OA, Fehintola FA, Gbotosho GO, Larcier P, Salako LA, 1998. Cardiac effects of halofantrine in children suffering from acute uncomplicated falciparum malaria. Trans R Soc Trop Med Hyg 92 :446–448.

    • Search Google Scholar
    • Export Citation
  • 9

    Nosten F, ter Kuile FO, Luxemburger C, Woodrow C, Kyle DE, Chongsuphajaisiddhi T, White NJ, 1993. Cardiac effects of antimalarial treatment with halofantrine. Lancet 341 :1054–1056.

    • Search Google Scholar
    • Export Citation
  • 10

    Touze JE, Fourcade L, Peyron F, Heno P, Deharo JC, 1997. Is halofantrine still advisable in malaria attacks? Ann Trop Med Parasitol 91 :867–873.

    • Search Google Scholar
    • Export Citation

 

 

 

 

SHORT REPORT: IN VIVO SENSITIVITY OF PLASMODIUM FALCIPARUM TO HALOFANTRINE IN SOUTHERN CENTRAL VIETNAM

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  • 1 U. S. Naval Medical Research Unit No. 2, Jakarta, Indonesia; Department of Tropical Medicine, Tulane University School of Public Health, New Orleans, Louisiana; Institute of Malariology, Parasitology, and Entomology, Hanoi, Vietnam

Drug-resistant Plasmodium falciparum is present in Vietnam. We assessed the in vivo sensitivity of P. falciparum to halofantrine in two villages in the southern part of central Vietnam. Halofantrine (8 mg/kg × 3 doses) was administered to 37 patients with either P. falciparum (n = 32) or mixed P. falciparum/P. vivax malaria (n = 5). End points were parasite sensitivity or resistance (RI/RII/RIII) determined by parasite clearance, persistence, or recurrence during 28 days of follow-up. By day 28, 31 (93.9%) of 33 (95% confidence interval = 79.8–99.2%) patients were sensitive. Two patients had recurrent P. falciparum parasitemia on days 14 and 21. Halofantrine effectively treated uncomplicated P. falciparum malaria in these Vietnamese patients.

In Vietnam, Plasmodium falciparum is resistant to commonly used antimamalarial drugs.1 In 1995, we investigated the sensitivity of halofantrine by conducting a 28-day in vivo test in two villages in Khanh Hoa province, 40 miles west of the coastal town of Nha Trang in southern central Vietnam. Malaria incidence rates in this area are 1.9 per person-year for P. falciparum, 1.1/person-year for P. vivax, and 0.03/person-year for P. malariae (Nhan DH, unpublished data). Written, informed consent was obtained from all participating patients or their parents/guardians. The study was conducted according to the Vietnamese Ministry of Health and the United States Navy regulations governing the protection of human subjects in medical research. Entry criteria and study conduct have been reported in detail elsewhere.2 Three doses of halofantrine (Glaxo SmithKline, London, United Kingdom), 8 mg/kg every six hours, was administered in the hospital on an empty stomach (at least one hour before or two hours after a meal) to patients with no clinical signs of cardiac disease and a normal QTc interval. Thick and thin film blood smears (days 1, 2, 4, 7, 11, 14, 18, 21, and 28) were stained with Giemsa, read, and the results were reported as parasites/microliter. Data were analyzed using Epi-Info version 6.04 (Centers for Disease Control and Prevention, Atlanta, GA).

There were 37 treated patients in the study: 32 with P. falciparum monoinfection and 5 with mixed P. falciparum/P. vivax malaria. Enrollment characteristics are shown in Table 1. On day 0, all patients were either symptomatic or febrile (oral temperature > 37°C). By day 28, four patients were lost to follow-up, and two patients with P. falciparum malaria developed recurrent P. falciparum parasitemia: a 17-year-old man on day 14 (day 0 parasitemia = 2,120/μL, recurrent parasitemia = 240/μL) and an eight-year-old girl on day 21 (day 0 parasitemia = 18,040/μL, recurrent parasitemia = 280/μL). Using a previously published method,3 we amplified the small subunit ribosomal RNA of P. falciparum by a polymerase chain reaction (PCR) to confirm the microscopic diagnosis of P. falciparum of the day 0/day recurrent (dayrec) slides. However, technical difficulties unfortunately precluded the genotyping the dayrec slides with merozoite surface protein-2 primers.3 When the four patients lost to follow-up were excluded, the 28-day cure rate was 31 (93.9%) of 33 (95% confidence interval = 79.8–99.2%). The P. falciparum parasite clearance rates were 16.2% by day 1, 73.0% by day 2, 91.4% by day 4, and 100% by day 7.

This study demonstrates the sensitivity of P. falciparum to halofantrine in one small area of southern central Vietnam. Recurrent parasitemia (n = 2) occurred on days 14 and 21, consistent with new infections, RI resistance, or treatment failures due to poor absorption of halofantrine.4 The expected number of new P. falciparum infections in our cohort of 33 who completed the four week follow-up is ≈5 (1.9 infections/person-year × 33 persons × 4 weeks × 1/52 years). These epidemiologic data favor new infections as the cause of our two cases of recurrent parasitemia. However, we cannot exclude drug resistance because of the failure of our PCR genotyping.

Mefloquine, but not halofantrine, was available in local shops when the study was conducted. Mefloquine is cross-resistant to halofantrine; thus, its use would be a factor in the generation of halofantrine resistance.5,6 Our study used the original World Health Organization (WHO) parasitologic in vivo test to assess halofantrine sensitivity. There is now a new WHO in vivo test for areas of intense and low/moderate malaria transmission that should be adopted as the standard test for defining drug resistance. Accordingly, our two cases of recurrent parasitemia would have been classified as either late parasitologic or clinical treatment failures, depending on whether they were febrile (axillary temperature ≥ 37.5°C.) at the time of their recurrent parasitemia.7

Halofantrine has potentially serious cardiotoxicity that restricts its use to specific clinical indications, e.g., drug-resistant P. falciparum malaria in patients with normal electrocardiographic findings who have not recently consumed drugs that prolong the QTc interval.8–10 These prerequisites make halofantrine unsuitable for widespread use in primary health settings of malaria-endemic countries.

Table 1

Enrollment characteristics of Vietnamese patients with Plasmodium falciparum (n = 32) or mixed P. falciparum/P. vivax (n = 5) malaria in a 28-day in vivo test assessing halofantrine sensitivity

Halofantrine group (n = 37)
* Number (%) consuming any antimalarial drug within one month of enrollment.
Defined as fever, chills, headache, myalgia, or anorexia.
Defined as an oral temperature > 37.0°C.
No. (%) of males23 (62.2)
Median (range) age in years12 (5–42)
Prestudy antimalarial drug use*13 (35.1)
No. (%) symptomatic28 (75.7)
No. (%) febrile31 (83.8)
Median (range) day 0 temperature, °C37.5 (36.3–39.5)
No. (%) with splenomegaly24 (64.9)
Median (range) P. falciparum parasitemia/μL400 (40–46,480)

Authors’ addresses: Doan Hanh Nhan, Nguyen Dieu Thuong, Tran Thi Uyen, and Le Dinh Cong, Institute of Malariology, Parasitology, and Entomology, Hanoi, Vietnam. Walter R. J. Taylor, World Health Organization/TDR/PRD, Centre Casai, 51-53 Avenue Louis, Casai 1216, Cointrin, Geneva, Switzerland, Telephone: 41-22-791-3853, Fax: 44-22-791-4774, E-mail: taylorw@who.ch. David J. Fryauff, Ika Susanti, Eduardo Gómez-Saladín, and J. Kevin Baird, U.S. Naval Medical Research Unit No. 2, Box 3, Unit 8132, APO, AP 96520-8132, Jakarta. Indonesia.

Acknowledgments: We are grateful to Drs. Luc Nguyen Tuyen (Khanh Hoa Provincial Antimalaria Office, Nha Trang, Vietnam), Le Minh Dao and Ta Thi Tinh (Institute of Malariology, Parasitology, and Entomology, Hanoi, Vietnam) for assistance with field execution; Pak Suradi (U.S. Naval Medical Research Unit No. 2) for assistance with data management; and Pak Purnomo and Pak Masbar for slide quality control.

Financial support: This study was supported by the U.S. Naval Medical Research and Development Command (Work Unit Number 63002A810.00101.HFX.1433).

Disclaimer: The views expressed in this article are those of the authors and do not in any way represent those of the U.S. Navy or the Vietnamese Ministry of Health.

REFERENCES

  • 1

    Thanh NV, Cowman AF, Hipgrave D, Kim TB, Phuc BQ, Cong LD, Biggs BA, 2001. Assessment of susceptibility of Plasmodium falciparum to chloroquine, quinine, mefloquine, sulfa-doxine-pyrimethamine and artemisinin in southern Vietnam. Trans R Soc Trop Med Hyg 95 :513–517.

    • Search Google Scholar
    • Export Citation
  • 2

    Taylor WR, Doan HN, Nguyen DT, Tran TU, Fryauff DJ, Gómez-Saladín E, Kain KC, Le DC, Baird JK, 2000. Assessing drug sensitivity of Plasmodium vivax to halofantrine or chloroquine in southern, central Vietnam using an extended 28-day in vivo test and polymerase chain reaction genotyping. Am J Trop Med Hyg 62 :693–697.

    • Search Google Scholar
    • Export Citation
  • 3

    Kimura M, Kaneko O, Liu Q, Zhou M, Kawamoto F, Wataya Y, Otani S, Yamaguchi Y, Tanabe K, 1997. Identification of the four species of human malaria parasites by nested PCR that targets variant sequences in the small subunit rRNA gene. Parasitol Int 46 :91–95.

    • Search Google Scholar
    • Export Citation
  • 4

    Milton KA, Edwards G, Ward SA, Orme ML, Breckenridge AM, 1989. Pharmacokinetics of halofantrine in man: effects of food and dose size. Br J Clin Pharmacol 28 :71–77.

    • Search Google Scholar
    • Export Citation
  • 5

    Basco LK, Le Bras J, 1992. In vitro activity of halofantrine and its relationship to other standard antimalarial drugs against African isolates and clones of Plasmodium falciparum.Am J Trop Med Hyg 47 :521–527.

    • Search Google Scholar
    • Export Citation
  • 6

    ter Kuile FO, Dolan G, Nosten F, Edstein MD, Luxemburger C, Phaipun L, Chongsuphajaisiddhi T, Webster HK, White NJ, 1993. Halofantrine versus mefloquine in treatment of multidrug-resistant falciparum malaria. Lancet 341 :1044–1049.

    • Search Google Scholar
    • Export Citation
  • 7

    World Health Organization, 2002. Monitoring Antimalarial Drug Resistance. Consultation, 2001. December 3–5, 2001. Geneva: World Health Organization, WHO/CDS/CSR/EPH/2002.17.

  • 8

    Sowunmi A, Falade CO, Oduola AM, Ogundahunsi OA, Fehintola FA, Gbotosho GO, Larcier P, Salako LA, 1998. Cardiac effects of halofantrine in children suffering from acute uncomplicated falciparum malaria. Trans R Soc Trop Med Hyg 92 :446–448.

    • Search Google Scholar
    • Export Citation
  • 9

    Nosten F, ter Kuile FO, Luxemburger C, Woodrow C, Kyle DE, Chongsuphajaisiddhi T, White NJ, 1993. Cardiac effects of antimalarial treatment with halofantrine. Lancet 341 :1054–1056.

    • Search Google Scholar
    • Export Citation
  • 10

    Touze JE, Fourcade L, Peyron F, Heno P, Deharo JC, 1997. Is halofantrine still advisable in malaria attacks? Ann Trop Med Parasitol 91 :867–873.

    • Search Google Scholar
    • Export Citation
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