Effects of Different Antimalarial Drugs on Gametocyte Carriage in P. Vivax Malaria

Sasithon Pukrittayakamee 0 1 Mallika Imwong 0 1 Pratap Singhasivanon 0 1 Kasia Stepniewska 0 1 Nicholas J. Day 0 1 Nicholas J. White 0 1 0 Medicine, Mahidol University , 420/6 Rajvithi Road, Bangkok 10400 , Thailand 1 Department of Tropical Medicine, Faculty of Tropical Medicine, Mahidol University , Bangkok , Thailand; The Royal Institute , Grand Palace, Bangkok , Thailand; Centre for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, Churchill Hospital , Oxford , United Kingdom The gametocytocidal and asexual stage activities of eight antimalarial and eight antibiotic-containing regimens were evaluated in 349 adult patients with P. vivax malaria. Gametocytemia was found in 63% of patients (22% before and 41% after treatment). The median (range) gametocyte clearance time was 24 hours (range, 2-504 hours) and correlated with asexual parasite clearance time (r 0.52, P < 0.001). Gametocytemia in vivax malaria was more common in patients with admission parasitemia > 10,000/L and after treatment with drugs which have weak antimalarial activity, and was also associated with an increased rate of vivax reappearance (29.4% versus 14.1%, P 0.002). Sexual stage activities corresponded with asexual stage activity for all tested regimens. Treatment with potent antimalarial drugs reduces the transmission potential of P. vivax. - Plasmodium vivax is the most prevalent human malaria species outside Africa, causing > 75 million acute malaria episodes per year in Central and South America and Asia, and it is increasingly recognized in Eastern Africa. Approximately 75% of P. vivax infections occur on the Asian continent with 1520% in Central and South America and the remaining 515% in Africa. P. vivax is generally sensitive to chloroquine, although high level resistance is now found on the islands of New Guinea and Sumatra and lower levels of resistance have been reported from an increasing number of other geographic locations in Asia and the Americas.14 In Thailand, where the current studies were performed, the prevalence of P. vivax is similar to that of P. falciparum, and mixed infection with the two species is common and underrecognized. Malaria transmission is determined by the frequency with which Anopheline mosquito vectors feed on human hosts carrying sufficient densities of sexual stages (gametocytes) in their peripheral blood.5,6 In falciparum malaria, gametocytogenesis is delayed with respect to asexual stage multiplication, whereas in the other three human malarias, sexual and asexual stage development are closer together.710 In P. falciparum malaria, primaquine accelerates clearance of gametocytes and artemisinin derivatives prevent gametocyte development, whereas most of the other antimalarial drugs have little or no effects on the development or viability of mature gametocytes.1114 In P. vivax malaria, the antimalarial drugs are all considered to be effective against the sexual stages of the parasite,15 although there have been no prospective studies on gametocytocidal activity or on the factors that influence the production of gametocytes in vivo in this infection. There is no in vitro model to test gametocytocidal drug activity against P. vivax directly because ex vivo culture is hampered by the requirement for special culture media16,17 and the lack of reproducible continuous culture methods. This study, conducted outside a malaria transmission area, evaluated and compared the sexual and asexual stage activities of the major MATERIALS AND METHODS Patients. The study was conducted in adult male patients with acute symptomatic Plasmodium vivax malaria admitted to the Bangkok Hospital for Tropical Diseases. The study took place during 19941998. In total 16 oral antimalarial regimens were tested for their asexual stage activity. Patients with microscopically detected asexual stages of both Plasmodium vivax and Plasmodium falciparum on admission (i.e., mixed infection) were excluded. Full details of the asexual stage antimalarial activities have been reported previously.18,19 The oral treatments consisted of eight first-line antimalarial drugs either alone or in combination and eight regimens containing antibiotics with known antimalarial activities as follows: 1) artesunate (Guilin Pharmaceutical Co., Guilin, China) 3.3 mg/kg followed by 1.65 mg/kg for the next 4 days; 2) artemether (Kunming Pharmaceutical Co., Kunming, China) 2.7 mg/kg followed by 1.3 mg/kg daily for the next 4 days; 3) chloroquine (Government Pharmaceutical Organization, Bangkok, Thailand) 25 mg base/kg total dose given over 3 days; 4) chloroquine 25 mg base/kg total dose given over 3 days followed by primaquine (Government Pharmaceutical Organization) 15 mg base/d for 14 days; 5) mefloquine (Roche, Basle, Switzerland) 15 mg base/kg single dose; 6) halofantrine (Glaxo SmithKline Laboratories, Brentford, UK) 8 mg base/kg three times in 1 day; 7) primaquine (Government Pharmaceutical Organization) 15 mg base/d for 14 days; 8) quinine sulfate (Government Pharmaceutical Organization) 10 mg salt/kg three times daily for 7 days; 9) sulfadoxine/pyrimethamine (Roche) 25/1.25 mg/kg (adult dose three tablets) single dose; 10) clindamycin (Upjohn Pharmaceuticals, Kalamazoo, MI) 300 mg four times daily for 7 days; 11) tetracycline (Government Pharmaceutical Organization) 250 mg four daily for 7 days followed by primaquine 15 mg base/d for 14 days; 12) tetracycline 250 mg daily for 7 days; 13) doxycycline (Siam Pharmaceutical, Bangkok, Thailand) 200 mg/d for 7 days; 14) azithromycin (Pfizer, Sandwich, UK) 500 mg/d for 3 days; 15) rifampicin (Marion Merrell Dow Pharmaceuticals, Kansas City, MO) 20 mg/kg/d followed by 15 mg/kg for the next 4 days followed by primaquine 15 mg base/d for 14 days; and 16) rifampicin 20 mg/kg/d followed by 15 mg/kg for the next 4 days. Oral paracetamol (0.51 g four times daily) was given for fever 38C. These studies were approved by the ethics committee of the Faculty of Tropical Medicine, Mahidol University, Bangkok. Full informed consent was given by all patients. Assessments of clinical response. Vital signs were recorded every 4 hours until resolution of fever and thereafter every 612 hours. Fever clearance time was defined as the time for body temperature to fall below 37.5C and remain below this value for > 48 hours. Early treatment failure was defined as persistence of fever and parasitemia for > 7 days or persistence of parasitemia in the absence of fever for > 14 days. Reappearance of infection was assessed in patients who remained in Bangkok either in the hospital or at home (i.e., outside the malaria transmission area) for at least 28 days. Patients who failed to respond to the treatment or those who had recurrent vivax infections were treated subsequently with the standard regimen of chloroquine and primaquine at that time (Regimen 4). Patients with delayed appearance of P. falciparum were treated with a 7-day course of quinine (10 mg (...truncated)