Chloroquine-resistant Plasmodium vivax, Brazilian Amazon.

To the Editor: Plasmodium vivax is the protozoan that causes the second most common form of malaria. Some resistant strains to chloroquine (CQ) occur in a few places in Asia and the Indo-Pacific Region (1-4). Although resistance of P. vivax to CQ has already been described in South America (5-7), there are limited data regarding this issue.

CQ plus primaquine is the standard treatment for vivax malaria worldwide. Presently, this drug regimen exhibits satisfactory efficacy in the Brazilian Amazon. However, in recent years several treatment failures presumably related to CQ resistance, have been reported in the city of Manaus (Amazonas) where vivax malaria predominates (7). This observation warrants local attention despite these cases having no confirmation of CQ blood levels on the basis of the appearance of asexual parasites against CQ plus desethylchloroquine levels exceeding the minimally effective plasma concentration proposed for sensitive parasite strains ([greater than or equal to] 10 ng/mL) (8), according to Pan American Health Organization recommendations (9).

From September 2004 to February 2005, a 28-day in vivo test was conducted at the Foundation for Tropical Medicine of Amazonas (FMTAM) in Manaus, Brazil, to assess the efficacy of standard supervised CQ therapy. The test involved 166 volunteers with uncomplicated vivax malaria. Each volunteer was administered uncoated, scored, 150-mg CQ tablets (10 + 7.5 + 7.5 mg/kg at 24-hour intervals) (9). Primaquine was withheld until day 28 (dose regimen of 30 mg/day for 7 days). Among the 109 volunteers who completed the in vivo test, 19 had positive blood smears within the 28-day follow-up (1 on day 14, 3 on day 21, and 15 on day 28). All were required to undergo alternative therapy (mefloquine). Adequate CQ absorption was confirmed in these cases on day 2 with a mean [+ or -] SD CQ plasma concentration of 785.4 [+ or -] 800.1 ng/mL) (10) Suspected therapeutic failure (P. vivax CQ resistance) was confirmed in 11 (10.1%) of 109 persons with a mean isolated choloroquine plasma concentration >10 ng/mL (356.6 [+ or -] 296.1 ng/mL) (9). Desethylchloroquine levels in plasma were not measured.

Previously, a CQ efficacy study demonstrated that 4.4% of those tested had CQ-resistant P. vivax (7). In comparison, the proportion of failures (10.1%) in the current study seems to be relevant; even though most of the P. vivax infections (98, 89.9%) were successfully evaluated and adequate clinical and parasitologic responses were obtained. Currently, the FMTAM Manaus Outpatient Clinic is detecting patients from different areas of the city who show parasitologic recurrences after correct treatment within 28 days of the routine clinical follow-up. This observation is an indirect indicator of the possible regional spread of P. vivax CQ-resistant strains (unpub. data).

We believe our findings are important and merit the attention of local public health authorities. Considering the possibility of emerging underestimated P vivax CQ resistance in Manaus, we feel it is essential to quickly clarify whether such documented resistance can copromote vivax malaria outbreaks in malaria-endemic areas within the Amazon.

This study was supported by the Brazilian Ministry of Health and the US Agency for International Development as part of the scientific program of the Amazonian Surveillance Network for Antimalarial Drugs Resistance (RAVREDA).

References

(1.) Marlar-Than, Myat-Phone-Kyaw, Aye-Yo-Soe, Khaing-Khaing-Gyi, Ma- Sabai, Myint-Oo. Development of resistance to chloroquine by Plasmodium vivax in Myanmar. Trans R Soc Trop Med Hyg. 1995:89:307-8.

(2.) Congpuong K, Na-Bangchang K, Thimasarn K, Tasanor U, Wernsdorfer WH. Sensitivity of Plasmodium vivax to chloroquine in Sa Kaeo Province, Thailand. Acta Trop. 2002;83: 117-21.

(3.) Hamedi Y, Nateghpour M, Tan-ariya P, Tiensuwan M, Silachamroon U, Looareesuwan S. Plasmodium vivax malaria in southeast Iran in 1999-2001: establishing the response to chloroquine in vitro and in vivo. Southeast Asian J Trop Med Public Health. 2002;33:512-8.

(4.) Baird JK, Wiady I, Fryauff DJ, Sutanihardja MA, Leksana B, Widjaya H, et al. In vivo resistance to chloroquine by Plasmodium vivax and PlasmodiuYm falciparum at Nabire, Irian Jaya, Indonesia. Am J Trop Med Hyg. 1997;56:627-31.

(5.) Phillips EJ, Keystone JS, Kain KC. Failure of combined chloroquine and high-dose primaquine therapy for Plasmodium vivax malaria acquired in Guyana, South America. Clin Infect Dis. 1996;23:1171-3.

(6.) Ruebush TK II, Zegarra J., Cairo EM, Andersen M, Green DR., Pillai W, et al. Chloroquine-resistant Plasmodium vivax malaria in Peru. Am J Trop Med Hyg. 2003;69:548-52.

(7.) Alecrim MGC. Estudo clinico, resistencia e polimorfismo parasitario na malaria pelo Plasmodium vivax, Manaus--AM. Brasilia: UNB, 2000. PhD Thesis, Faculdade de Medicina, Nucleo de Medicina Tropical, Universidade de Brasilia, 2000.

(8.) Baird JK, Leksana B, Masbar S, Fryauff DJ, Sutanihardja MA, Suradi FS, et al. Diagnosis of resistance to chloroquine by Plasmodium vivax: timing of recurrence and whole blood levels. Am J Trop Med Hyg. 1997;56:621-6.

(9.) Pan-American Health Organization. Generic protocol for antimalarial drug-efficacy studies in the Americas. Efficacy of chloroquine for the treatment of Plasmodium vivax malaria. 2004. [cited 2007 May 15]. Available from http://www.paho.org/english/AD/DPC/CD/mal-antimalarials.htm

(10.) Yonemitsu K, Koreeda A, Kibayashi K, Ng'walali P, Mbonde M, Kitinya J, et al. HPLC analysis of anti-malaria agent, chloroquine in blood and tissue from forensic autopsy cases in Tanzania. Leg Med (Tokyo). 2005;7:113-6.

Address for correspondence: Franklin Simoes de Santana Filho, The Foundation for Tropical Medicine of Amazonas, Av Pedro Teixeira 25 Planalto, Manaus, Amazonas 69040000, Brazil; email: [e-mail]

Franklin Simoes de Santana Filho, * Ana Ruth de Lima Arcanjo, * Yonne Melo Chehuan, * Monica Regina Costa, * Flor Ernestina Martinez-Espinosa, * ([dagger]) Jose Luis Vieira, ([double dagger]) Maria das Gracas Vale Barbosa, * ([section]) Wilson Duarte Alecrim, * ([paragraph]) and Maria das Gracas Costa Alecrim * ([section]) ([paragraph])

* Foundation for Tropical Medicine of Amazonas, Manaus, Amazonas, Brazil; ([dagger]) Foundation for Research Support of Amazonas, Manaus, Amazonas, Brazil; ([double dagger]) Federal University of Para Belem, Para, Brazil; ([section]) Amazonas State University, Manaus, Amazonas, Brazil; and ([paragraph]) Nilton Lins University, Manaus, Amazonas, Brazil