Malaria Prophylaxis Using Azithromycin: A Double-Blind, Placebo-Controlled Trial in Irian Jaya, Indonesia

74 Malaria Prophylaxis Using Azithromycin: A Double-Blind, Placebo-Controlled Trial in Irian Jaya, Indonesia Walter R. J. Taylor, Thomas L. Richie, David J. Fryauff, Helena Picarima, Colin Ohrt, Douglas Tang, David Braitman, Gerald S. Murphy, Hendra Widjaja, Emiliana Tjitra, Asep Ganjar, Trevor R. Jones, Hasan Basri, and Josh Berman From the U.S. Naval Medical Research Unit Number 2, Jakarta, Indonesia; the Department of Tropical Medicine, Tulane University School of Public Health, New Orleans, Louisiana, the Division of Experimental Therapeutics and the Division of Biometrics, Walter Reed Army Institute of Research, Washington, D.C., and the U.S. Army Medical Materiel Development Activity, Fort Dietrick, Maryland, USA; and the Centre for Health Research and Development, National Institutes of Health, and the District Military Health Services, Jayapura, Irian Jaya, Indonesia Malaria is a serious global public health problem. The World Health Organization estimates that there are 300 – 500 million cases of clinical malaria each year worldwide with 1.5 to 2.7 million deaths attributable to Plasmodium falciparum [1, 2]. Chemoprophylaxis for malaria is aimed at two distinct groups: nonimmune individuals of all ages who travel to areas where malaria is endemic [3] and pregnant women living in areas of endemicity [4]. Antimalarial drugs for prophylaxis and treatment are becoming increasingly ineffective because of the continuing rise of multidrug-resistant P. falciparum malaria in most areas where malaria is endemic [5, 6]. Malaria due to Received 6 May 1998; revised 24 August 1998. Informed consent was obtained from all study subjects, and the regulations governing the protection of human subjects of the Indonesian Ministry of Health, the Indonesian Army, and the U.S. Navy and Army were followed in the conduct of this study. The views expressed in this article are those of the authors and do not in any way represent those of the Indonesian Army, the Indonesian Ministry of Health, or the U.S. Army and Navy. Financial support: This study was supported by the U.S. Army Medical Materiel Development Activity and the U.S. Naval Medical Research and Development Command (Department of Defense funding reference; 65807/ 849/QG). Reprints: Publications Office, US NAMRU-2, Box 3, Unit 8132, APO, AP 96520-8132, USA. Correspondence: Dr. W. R. J. Taylor, 26, Pitchford Road, Shrewsbury, Shropshire, SY1 3HS, United Kingdom (). Clinical Infectious Diseases 1999;28:74–81 q 1999 by the Infectious Diseases Society of America. All rights reserved. 1058–4838/99/2801–0012$03.00 / 9c5e$$ja06 12-28-98 16:19:37 chloroquine-resistant Plasmodium vivax is now an emerging threat [7, 8]. Prophylactic drugs must have high efficacy and low toxicity. Mefloquine, doxycycline, and chloroquine/proguanil are currently recommended as prophylaxis for chloroquine-resistant P. falciparum malaria [3, 9, 10]. None of these drugs is ideal. Doxycycline is contraindicated in pregnancy [3, 10] and children younger than 8 years of age [9]. Mefloquine is contraindicated for patients with a history of epilepsy or serious psychiatric disease [9]. The World Health Organization [3] and the British authorities [10] recommend avoidance of mefloquine in the first trimester of pregnancy, but the Centers for Disease Control and Prevention support the use of mefloquine if travel to an area where chloroquine-resistant malaria occurs is unavoidable [9]. Chloroquine and proguanil are safe in pregnancy [10, 11], but this combination has low efficacy [12, 13]. Azithromycin, an azalide antibiotic similar to erythromycin, had good antimalarial activity in human malaria challenge studies [14, 15]. When azithromycin was used for treating Gambian children with trachoma, spleen rates, parasite counts, and the number of episodes of febrile parasitemia due to P. falciparum were coincidentally reduced [16]. In a malaria prophylaxis trial in Kenyan adults, 250 mg of azithromycin daily had a prophylactic efficacy against P. falciparum malaria based on crude incidence of 83% (95% CI, 68 – 91) [17]. Azithromycin can be used by pregnant and breast-feeding women and children older than 6 months of age [18]. If the measured prophylactic efficacy against P. falciparum malaria cida UC: CID New drugs are needed for preventing drug-resistant Plasmodium falciparum malaria. The prophylactic efficacy of azithromycin against P. falciparum in malaria-immune Kenyans was 83%. We conducted a double-blind, placebo-controlled trial to determine the prophylactic efficacy of azithromycin against multidrug-resistant P. falciparum malaria and chloroquine-resistant Plasmodium vivax malaria in Indonesian adults with limited immunity. After radical cure therapy, 300 randomized subjects received azithromycin (148 subjects, 750-mg loading dose followed by 250 mg/d), placebo (77), or doxycycline (75, 100 mg/d). The end point was slide-proven parasitemia. There were 58 P. falciparum and 29 P. vivax prophylaxis failures over 20 weeks. Using incidence rates, the protective efficacy of azithromycin relative to placebo was 71.6% (95% confidence interval [CI], 50.3 – 83.8) against P. falciparum malaria and 98.9% (95% CI, 93.1 – 99.9) against P. vivax malaria. Corresponding figures for doxycycline were 96.3% (95% CI, 85.4 – 99.6) and 98% (95% CI, 88.0 – 99.9), respectively. Daily azithromycin offered excellent protection against P. vivax malaria but modest protection against P. falciparum malaria. CID 1999;28 (January) Azithromycin Prophylaxis for Malaria for a population with low or no immunity were high, then azithromycin would be a substantial addition to the present pool of prophylactic drugs. We report the protective efficacy of daily azithromycin given to Indonesian adults with limited immunity to malaria who resided in an area where multidrug-resistant P. falciparum malaria and chloroquine-resistant P. vivax malaria occur. Methods Study Design Study Site and Participants The study took place between July 1996 and January 1997 in Arso (a rural part of northeast Irian Jaya, close to Jayapura) where multidrug-resistant P. falciparum malaria [20–23] and chloroquine-resistant P. vivax malaria [8, 24] occur; the incidence rates (IRs) of P. falciparum and P. vivax infections have been documented as 3 cases per year [19, 25] and 2.5 cases per year [19], respectively. Entomological inoculation rates vary between 0.54 and 11.7 infective bites per person per month [25]. We recruited Indonesian Army soldiers from posts that were located near villages and housed Ç12 men. They had arrived 6 months earlier from southern Sumatra and were taking doxycycline, chloroquine, or sulfadoxine pyrimethamine as malaria prophylaxis (the latter two drugs were changed to doxycycline after the arrival of our team). Civilians were immigrant farmers from Java who were residents in one village (Arso PIR V) for 15 months. They had received free chloroquine prophylaxis during the first 3 month (...truncated)