Chemoprophylaxis and the epidemiological characteristics of re-emergent P. vivax malaria in the Republic of Korea.

827Bulletin of the World Health Organization | October 2006, 84 (10) Objective In the Republic of Korea (ROK), soldiers stationed where there is a risk of contracting malaria have received antimalarial chemoprophylaxis since 1997. However, chemoprophylaxis may facilitate the development of drug resistance, and late primary attacks in individuals who have received chemoprophylaxis are becoming more frequent. We investigated the association between chemoprophylaxis and the epidemiological characteristics and effectiveness of treatment for re-emergent Plasmodium vivax malaria, using a nationwide malaria database. Methods Among soldiers at risk of malaria between 1999 and 2001, we reviewed all P. vivax malaria cases (1158) that occurred before 31 December 2003. Early and late primary attacks were defined as cases occurring < 2 or > 2 months after the last day of exposure to risk of malaria, respectively. Findings Of these cases, 634 (72.0%) had received chemoprophylaxis, and 324 (28.0%) had not. Cases occurred mostly in summer, with a peak in July–August. Stratification by chemoprophylaxis history revealed different times to onset. Early primary attacks were more prevalent in the group not receiving chemoprophylaxis, while in the group receiving chemoprophylaxis most cases were late primary attacks. Of the latter, 312 out of 461 (67.7%) did not take primaquine regularly. After treatment of the first attack, 14 (1.2%) of 1158 were re-treated; all re-treated cases were cured using the same doses and regimen used for the first treatment. Conclusion In ROK, the increase in late primary episodes of re-emergent P. vivax malaria is associated with the use of antimalarial chemoprophylaxis. Bulletin of the World Health Organization 2006;84:827-834. Voir page 833 le résumé en français. En la página 833 figura un resumen en español. Introduction Plasmodium vivax, the causative agent of vivax malaria, has been endemic in the Republic of Korea (ROK) for cent turies. The number of cases of endemic malaria began to decline in the 1960s, partly due to increased socioeconomic development, increased use of agricult tural pesticides, and the efforts of the National Malaria Eradication Service. These factors contributed to the eradicat tion of malaria in the ROK, resulting in the declaration by WHO in 1979 that the country was malariatfree.1 In 1993, one case of malaria attributed to autot chthonous transmission was detected near the demilitarized zone (DMZ) that separates ROK (south) from the Democratic People’s Republic of Korea (north).2 Since 1993, the number of malaria cases has increased exponentially, particularly among soldiers based near the DMZ.1–5 Chemoprophylaxis and the epidemiological characteristics of re-emergent P. vivax malaria in the Republic of Korea Changsoo Kim,a Dong Chun Shin,a Tai Soon Yong,b Dae Kyu Oh,c Rock Kwon Kim,d Keeho Park,c & Il Suh a .833 ةحفص في ةيبرعلاب صخللما لىع علاطلاا نكيم a Department of Preventive Medicine, Yonsei University College of Medicine, 134 Shinchon-Dong, Seodaemun-Gu, Seoul 120-752, Seoul, Republic of Korea. Correspondence to Il Suh (email: isuh@yumc.yonsei.ac.kr). b Department of Parasitology, Yonsei University College of Medicine, Seoul, Republic of Korea. c Korea Center for Disease Control and Prevention, Seoul, Republic of Korea. d The Armed Forces Medical Command, Seoul, Republic of Korea. Ref No. 05-029546 (Submitted: 29 December 2005 – Final revised version received: 3 April 2006 – Accepted: 18 April 2006) In ROK, healthy males aged over 18 years serve 26 months of mandat tory military duty; most are stationed throughout their service near the DMZ, where the risk of malaria is highest. After finishing their military duty, the soldiers return from these risk areas to areas with little or no malaria. To reduce the occurrence of malaria among curt rent and former soldiers, the military initiated antimalarial chemoprophylaxis in 1997. Although chemoprophylaxis ret duces the number of cases of malaria, longtterm chemoprophylaxis can fat cilitate the development of drug resist tance.6,7 Recently, although there have been no reports of treatment failure in ROK, an increase in late primary epit sodes of P. vivax malaria among soldiers who had received chemoprophylaxis has raised doubts regarding its effectivet ness. A recent study in ROK showed that prophylaxis with primaquine was not effective in preventing late primary attacks.8 We investigated the association between chemoprophylaxis and the epidemiological characteristics and eft fectiveness of treatment for retemergent P. vivax malaria, using a nationwide malaria database. Methods Chemoprophylaxis Chemoprophylaxis with hydroxychlorot quine sulfate (400 mg, once per week) is started in early summer and continued throughout the transmission season. Fourteentday prophylaxis with primat quine (15 mg of base, once per day) is started on the first day of the last week of chloroquine administration. During military duty, soldiers assigned to areas at risk of malaria experience two cont secutive transmission seasons and ret ceive chemoprophylaxis each season. In 828 Bulletin of the World Health Organization | October 2006, 84 (10) Research Chemoprophylaxis and re-emergent P. vivax malaria in the Republic of Korea Changsoo Kim et al. addition to chemoprophylaxis, in 1998 the military adopted the use of permet thrinttreated battletdress uniforms and bednets, and the application of mosquito vectortcontrol agents. The number of soldiers receiving chemoprophylaxis and the amount of permethrin used have increased annually (Table 1). Malaria surveillance In ROK, malaria cases in soldiers must be reported to the Armed Forces Medit cal Command, and cases in veterans and civilians must be reported to the Korea Center for Disease Control and Prevent tion.4,9 Malaria cases in veterans are defined as those experiencing a malaria attack within 24 months after retiret ment. Soldiers diagnosed with malaria are admitted to a military hospital for treatment and are interviewed by physit cians; veterans are treated in community outpatient clinics and are interviewed by trained publicthealth specialists. All solt diers and veterans diagnosed with P. vivax malaria receive standard treatment: 2 g of hydroxychloroquine sulfate (1200, 400, and 400 mg on days 1 to 3, respectively) and 210 mg of primaquine (15 mg of base, once per day for 14 days). Study subjects We reviewed all cases of P. vivax malaria reported to the Armed Forces Medical Command and Korea Center for Disease Control and Prevention that occurred before 31 December 2003 in soldiers who had entered the ROK army during nontrisk periods between 1 October 1998 and 28 February 2001 and who had been exposed to risk of malaria for the first time in military service between 1999 and 2001. We defined the malaria risk period as 1 May to 30 September. Cases in soldiers who had entered the ROK army between 1 March and 30 Table 1. Antimalarial chemoprophylaxis and insecticide-treated materialsa received by soldiers in the Republic of Korea army Precaution Year 1999 2000 2001 2002 Chemoprophylaxis (No. of soldiers) 61 772 90 000 109 476 141 780 Period of chemoprophylaxis: Chloroquineb 7 June–11 October 5 June–9 October 14 May–24 September 13 May–23 September Primaquinec 12–25 October 3–16 October 18 September–1 October 17–30 September Insecticide-treated materialsa (No. of soldiers) 80 000 80 000 150 692 157 361 a Permethrin (6.4 g per person for 3 months) was used to treat battle-dress uniforms and bednets. b Hydroxychloroquine sulfate at a weekly dose of 400 mg. c Primaquine base at a daily dose of 15 mg. April (who would retire during a malaria risk period) or who retired during a mat laria risk period were excluded because we could not discriminate between early (individuals infected in the year of retiret ment) and late (individuals infected in the year before retirement) primary att tacks. Therefore, the subjects exposed to risk of malaria for the first time between 1999 and 2001 were those who had entered military service between the bet ginning of October 1998, 1999, or 2000 and the end of the respective following February 1999, 2000 or 2001. During the study period, 1215 cases of P. vivax malaria were reported. Of these, 56 in soldiers who had been in malaria risk areas after retirement (46 received chemoprophylaxis during milit tary duty and 10 did not) and one case from Africa were excluded. Ultimately, 1158 cases were analysed. Statistical analysis Cohorts of individuals exposed to risk of malaria in each year between 1999 and 2001 were constructed. Early and late primary attacks were defined as cases occurring < 2 or > 2 months after the last day of the malaria risk period, respectively. This study included all cases that occurred among defined populations; we therefore fixed the denominator in the chemoprophylaxis and notchemot prophylaxis groups such that the cases represent the epidemiological charactert istics of P. vivax malaria in each group. To analyse the proportional difference in early and late primary attacks between the groups that did or did not receive chemoprophylaxis, we divided the 1158 cases into two groups according to the timing of symptom onset (“before” and “after” the second round of chemoprot phylaxis began) because the number of soldiers receiving chemoprophylaxis changed each year. All cases that were primary attacks were followed until 31 December 2003 after treating the first attack. Ethical issues This study was approved by the Ethical and Security Committee for clinical research at Office of Surgeon General, Army Headquarters, Gyeryong, Republic of Korea. Table 2. Cases of P. vivax malaria in soldiers and veterans of the Republic of Korea army, by exposure cohort First year of exposure No. of patientsa Onset of symptomsb First yearc Second yeara Third yeara 1999 590 (209) 28 351 (2) 211 (207) 2000 370 (138) 30 201 139 (138) 2001 198 (80) 10 106 82 (80) Total 1158 (427) 68 657 (2) 432 (425) a Figures in parentheses are numbers of cases that occurred after retirement. b In the first and second year of follow-up, all cases were among soldiers exposed to risk of malaria; in the third year of follow-up, no cases were exposed to risk of malaria. c Cases that occurred in the first year of exposure. 829Bulletin of the World Health Organization | October 2006, 84 (10) Research Chemoprophylaxis and re-emergent P. vivax malaria in the Republic of Korea Changsoo Kim et al. Results Of the 1158 cases, 634 (72.0%) had ret ceived chemoprophylaxis during military duty, and 324 (28.0%) had not. All cases were among soldiers stationed in malaria risk areas during military duty. The year of symptom onset for each exposure cohort is shown in Table 2. Most cases occurred in summer (May– August), with a peak in July–August. In winter (December–February), only 12 cases (4, 7, and 1 in the first, second and third winters, respectively) occurred (Fig. 1). To investigate the monthly distribution of early and late primary attacks by history of chemoprophylaxis, we analysed the cases that occurred in the first and third years; cases that occurred in the second year were excluded in the analysis because early and late primary attacks occurred concurrently. Of the cases (mostly early primary attacks) that occurred in the first year, numbers in the notchemoprophylaxis group peaked before those in the chemoprophylaxis group, while the monthly distribution of cases (late primary attacks) that occurred in the third year was similar in the two groups (Fig. 2). Of the 1158 cases, 195 (16.8%) occurred before, and 963 (83.2%) after the second round of chemoprophylaxis started. Stratification of the cases on the basis of history of chemoprophylaxis revealed different times to onset (Fig. 3). The number of malaria cases in the notchemoprophylaxis group increased within 5 months of first exposure to mat laria risk, as seen in Fig. 3a (72.2%) and Fig. 3b (77.3%). In the group receiving chemoprophylaxis, however, most cases occurred after 10 months, as seen in Fig. 3a (84.6%) and Fig. 3b (58.2%). Of the 195 cases that occurred before the start of the second round of chemoprophylaxis, 107 (87.0%) of the 123 cases in the group receiving chemoprophylaxis and 20 (27.8%) of the 72 cases that did not receive chemot prophylaxis were late primary attacks (Table 3). All the cases in the group receiving chemoprophylaxis received chloroquine, and 44 (41.1%) of the 107 cases that were late primary attacks finished prophylaxis with primaquine. Of the 963 cases that occurred after the second round started, 354 (59.2%) of the 598 cases in the group receiving chemoprophylaxis and 79 (21.6%) of the 365 cases who did not receive the second chemoprophylaxis were late primary attacks. Of the 354 cases that were late primary attacks and who received the second chemoprophylaxis, 105 (29.7%) completed prophylaxis with primaquine. After using the history of first chet moprophylaxis to stratify the 963 cases that occurred after the start of the second round, the proportion of late primary attacks was found to be significantly higher among cases who received the second chemoprophylaxis than among those who did not, regardless of first chemoprophylaxis history (Table 4, web version only, available from: http://www. who.int/bulletin). After the first attack had been treated, 14 (1.2%) out of 1158 cases were rettreated for P. vivax malaria. All the first attacks occurred during military duty; in seven cases, a second attack oct curred after retirement. A third episode of P. vivax malaria occurred in one case within 1 month after the second attack during military duty. After excluding Fig. 1. Monthly distribution for cases of P. vivax malaria in soldiers and veterans of the army of the Republic of Korea, for each exposure cohort N o. o f p at ie nt s 90 Month 5 (May) 0 a) 1999 80 70 60 50 40 30 20 10 1st risk period 1st year 2nd risk period Before retirement After retirement 2nd year 3rd year N o. o f p at ie nt s 0 b) 2000 70 60 50 40 30 20 10 1st risk period 2ndrisk period N o. o f p at ie nt s 0 c) 2001 exposure cohorts 30 5 1st risk period 2nd risk period 25 20 15 10 N o. o f p at ie nt s 0 d) 3-year pooled data 180 1st risk period 2ndrisk period 160 140 120 100 80 60 40 20 6 7 8 9 1011 12 1 (Jan) 2 3 4 5 6 7 8 9 10 11 12 1 (Jan) 2 3 4 5 6 7 8 9 101112 830 Bulletin of the World Health Organization | October 2006, 84 (10) Research Chemoprophylaxis and re-emergent P. vivax malaria in the Republic of Korea Changsoo Kim et al. the cases that occurred in 2003 (relapses would have occurred in 2004 or later), 484 out of 1076 cases were not exposed to risk of malaria after the first diagnosis. Of the 484 cases, 2 (0.4%) were rettreated as P. vivax malaria > 6 months (204 and 351 days) after the first attack. All rettreated cases were cured using the same doses and regimen used for the first treatment. Discussion Early primary attacks are usually defined as cases occurring < 1 month after exposure 10,11; however, to investigate the epidemiological characteristics of retemergent P. vivax malaria, we det fined early onset as cases occurring < 2 months after the last day of the malaria risk period (before December). Cases that occurred in the first year (i.e. cases infected in the first year) and third year (i.e. cases with infections from the pret vious year) showed a typical unimodal peak in summer, regardless of the history of chemoprophylaxis, and only a few cases occurred in winter (Fig. 2). Thus it is obvious that early primary attacks occurred before winter. The cases that occurred in November might have been caused by infection in late September or early October; therefore, we categorized all the cases that occurred in November as early primary attacks. In this study, most cases occurred in summer, with a peak in July–August, and the monthly distribution paralleled the density of the mosquito populat tion.12 After stratification by history of chemoprophylaxis, symptom onset in cases occurring in the first year was delayed in the group receiving chemot prophylaxis compared with that in the notchemoprophylaxis group, while it was similar in both groups for the cases that occurred in the third year. This sugt gests that bloodtstage schizonticide (by chloroquine) is associated with delayed symptom onset and that the latency pet riod of late primary attack is not related to chemoprophylaxis. Studies conducted between about 1950 and the 1970s demonstrated that Korean P. vivax malaria had both short and long latency periods and that most cases had a long latency, characteristic of P. vivax malaria in temperate regions.13–15 A recent study also suggested that twot thirds of retemergent cases of P. vivax malaria had a long latency, with a mean duration of 10 months, although longt latency forms of P. vivax malaria might have been overrepresented because only cases that occurred after retirement were included.16 Unlike previous studies, most cases in this study involving soldiers and veterans that did not receive chemot prophylaxis were early primary attacks, while most cases that received chemot prophylaxis were late primary attacks. These findings suggest that retemergent P. vivax malaria has epidemiological characteristics that differ from those of the P. vivax malaria that was in existence between about 1950 and the 1970s, but that are similar to those of tropical strains, which have a short latency period before symptom onset.13 Moreover, the use of antimalarial chemoprophylaxis can change the pattern of malaria oct currence. Although genetic evidence suggests that retemergent P. vivax has a Chinese or Democratic People’s Republic of Korean origin,17,18 genetic variation might have arisen in response to chemot prophylaxis or climate change. A recent study demonstrated that the merozoite surface protein (MSP) gene nucleotide sequence of P. vivax in ROK is similar to that of Thai isolates.19 However, we can not conclude that our results show evidence of tropical strains in ROK because strain characterization was not performed. To identify the biological characteristics and origin of retemergent P. vivax malaria, further molecular epit demiological analysis is needed. Fig. 2. Monthly distribution of cases of P. vivax malaria during the first and third years of follow-up in soldiers and veterans of the army of the Republic of Korea Total N o. o f p at ie nt s 30 Month 5 0 No chemoprophylaxis Chemoprophylaxis 0 10 15 20 25 6 7 8 9 10 11 12 N o. o f p at ie nt s Month 1 0 20 40 60 140 120 100 80 2 3 4 5 6 7 8 9 10 11 12 Total No chemoprophylaxis Chemoprophylaxis a) Cases that occurred in the first year b) Cases that occurred in the third year 831Bulletin of the World Health Organization | October 2006, 84 (10) Research Chemoprophylaxis and re-emergent P. vivax malaria in the Republic of Korea Changsoo Kim et al. Most late primary attacks (312 of 461 cases, or 67.7%) in the group receivt ing chemoprophylaxis were in soldiers who had not taken primaquine prophyt laxis regularly, implicating nontadhert ence to prophylaxis as a major cause of the increase in late primary attacks. Two additional factors might have affected the observed increase in late primary attacks among those who had received chemoprophylaxis. First, primaquine may not effect tively reduce late primary attacks; a recent study in ROK reported that the effectiveness of primaquine prophylaxis against late primary attacks was 32%,8 and that the doses of primaquine used in ROK would be considered inadequate in other countries.20–24 In this study, late primary attacks occurred in individuals who had received primaquine prophyt laxis regularly, and it is thus possible that factors such as inadequate primaquine dosage and absorption are associated with P. vivax malaria. However, only 0.4% of those receiving the standard prophylactic dose of primaquine were rettreated for relapse, suggesting that primaquine effectively reduces the incit dence of late primary attacks. Second, symptom onset might be masked in patients receiving chet moprophylaxis because of bloodtstage schizonticidal activity; consequently, the number of late primary attacks might increase. This hypothesis is supported by two findings: (1) the stratification of cases by history of chemoprophyt laxis revealed delayed symptom onset in early primary attacks and a different proportion in late primary attacks; and (2) 32.3% of late primary attacks in the group receiving chemoprophylaxis were in men who had taken chloroquine and primaquine. Interestingly, in this study, cases of delayed symptom onset did not occur immediately after the end of chloroquine prophylaxis and convert into late primary attacks. Owing to det sign limitations, we could not find any determinants associated with the latency of P. vivax malaria, and further investigat tions are needed. For these two reasons, the increase in late primary attacks in the group ret ceiving chemoprophylaxis may be largely associated with patient nontadherence to primaquine and a delay in symptom onset attributable to chemoprophyt laxis. These findings are important not only for planning chemoprophylaxis Fig. 3. Cumulative percentage of P. vivax malaria cases that occurred before and after the start of the second round of chemoprophylaxis Cu m ul at iv e pe rc en ta ge o f c as es 100 Months since the first exposure to malaria risk 0 (May) 0 No chemoprophylaxis Chemoprophylaxis a) Cases occurring before the second round of chemoprophylaxisa (n = 195) b) Cases occurring after the second round of chemoprophylaxisb (n = 963) 50 1 2 3 4 5 6 7 8 (Jan) 9 10 11 12 13 Cu m ul at iv e pe rc en ta ge o f c as es 100 Months since the second exposure to malaria risk 0 (May) 0 No chemoprophylaxis Chemoprophylaxis 50 1 2 3 4 5 6 7 8 (Jan) 9 10 11 12 13 14 15 16 17 18 19 a Using the history of first chemoprophylaxis. b Using the history of second chemoprophylaxis. programmes for areas with little or no malaria risk, because late primary attacks can directly affect the spread of malaria, but also for assessing the effectiveness of prophylaxis with primaquine, because chloroquine is a powerful potential confounding factor.25 If the effects of chloroquine are not considered, the eft ficacy of prophylaxis with primaquine could be significantly underestimated owing to symptom onset delay.8 Primaquine is the only available drug that eliminates livertstage parat sites, although other drugs such as tafenoquine and malarone are being tested.20,26,27 Primaquine is a longtterm medication (usually 14 days), and low compliance can be a problem.28 To increase compliance, the ROK military requires that all soldiers take antimalarial drugs under direct supervision and sign a drug administration checklist. In adt dition, to reduce late primary attacks occurring after retirement, all soldiers who were stationed in risk areas and retiring during the malaria risk period receive primaquine prophylaxis before retirement. Nevertheless, for a variety of reasons, low compliance with chet moprophylaxis remains a major problem 832 Bulletin of the World Health Organization | October 2006, 84 (10) Research Chemoprophylaxis and re-emergent P. vivax malaria in the Republic of Korea Changsoo Kim et al. in ROK. In this study, most of those who had late primary attacks had not taken primaquine regularly. Thus, to effectively reduce malaria among soldiers and veterans, a continuing education programme and strict compliance with chemoprophylaxis are essential. Some studies have suggested that, because mass antimalarial chemoprot phylaxis in endemic areas dose not ret duce malaria transmission, other prevent tive measures such as insecticidettreated battle dress uniforms and bednets, and residual spraying are critical for controlt ling transmission.6,7,29 The situation in ROK is unusual because sporozoitet infected mosquitoes moving from north to south across the DMZ caused the retemergence of malaria.30,31 Although malaria has spread south of the DMZ, most cases still occur near the DMZ.32 Moreover, a state of military confrontat tion still exists along the DMZ. For these reasons, the goals of chemoprophylaxis in the ROK military are to reduce the number of malaria cases and to limit the spread of malaria into nontrisk areas. On the basis of our results, it is impossible to determine whether chemoprophylaxis should be encouraged or discouraged to reduce the number of late primary attacks. If chemoprophylaxis were to be discontinued, the number of late primary attacks would increase with the total number of malaria cases. Cont versely, although no report on treatment failure has been issued, the continuation of longtterm chemoprophylaxis might enhance resistance or tolerance to ant timalarial drugs. Given that most cases occurring during April and May are late primary attacks from the previous year, chemoprophylaxis and other prevention measures should be started at the begint ning of April to reduce the potential for transmission to humans. However, the best way to control P. vivax malaria in the Korean peninsula is to ensure that malaria eradication programmes are performed in the Democratic People’s Republic of Korea and in ROK. Although the ROK Government has supported malariatprevention programmes in the Democratic People’s Republic of Korea since 2001, and in 2005 provided the equivalent of US$ 877 000 of malariat related aid and equipment via WHO,33 support for aid programmes must be continued and extended. Our study has several limitations. First, misclassification bias could be a major limitation. Both early and late primary attacks occurred concurrently during the malaria risk period in the second year, and the secondtyear cases were categorized as early or late accordt ing to the timing of symptom onset. However, many of the cases that oct curred between May and early June (before chemoprophylaxis started) in the second year might actually have been late primary attacks in individuals infected in the first year, given that only two cases occurred between May and June in the first year. Considering the cases that oct curred before the second round of chet moprophylaxis and excluding 87 cases (76 in the chemoprophylaxis group; 11 in the notchemoprophylaxis group) that occurred after 1 May in the second year, the proportion of late primary att tacks was also significantly higher in the chemoprophylaxis group (66.0% versus 14.8%). It was impossible to distinguish early and late primary attacks during and after the malaria risk period in the second year. However, among the cases presenting before the second round of chemoprophylaxis, late primary attacks were more prevalent in the group receivt ing chemoprophylaxis, suggesting that the proportional difference between the chet moprophylaxis and notchemoprophylaxis groups in late primary attacks occurring after the start of the second round can be considered to be a conservative estimate, and thus it appears that our results are not greatly affected by misclassification bias. The second limitation is that the number of late primary attacks might have been overtestimated because gamet tocytetbearing subjects can reintroduce malaria to mosquitoes outside the risk area. However, the number of secondary and tertiary transmitted cases was probt ably small and is unlikely to have affected our results, because no cases among soldiers and few civilian cases (23 out of 609 cases in 2003) were reported in nontrisk areas during the study period, and most of those cases had a history of travel to malaria risk areas.5 Conclusions Despite its limitations, our study demont strates that retemergent P. vivax malaria in ROK shows epidemiological characterist tics that differ from those of the P. vivax malaria that existed between about 1950 and the 1970s, and that the increase in late primary episodes of retemergent P. vivax malaria is significantly associated with the use of antimalarial chemoprophylaxis. Although no treatment failures have been reported in ROK, further investigations of malariatprevention strategies are needed to ensure control of late primary episodes of P. vivax malaria and to prevent the det velopment of resistance or tolerance to antimalarial drugs. O Acknowledgments We thank Terry A Klein, Minh C Hoang, Youngkeun Kim, and Donghoon Ko for their comments on an early version of the manuscript. Competing interests: none declared. Table 3. Cases of P. vivax malaria that occurred before or after the start of the second round of chemoprophylaxis in soldiers and veterans of the Republic of Korea army Chemoprophylaxis No. of patients Latency period P-valuea Early Late Beforeb Yes 123 (100)c 16 (13.0) 107 (87.0) < 0.001 No 72 (100) 52 (72.2) 20 (27.8) Total 195 (100) 68 (34.9) 127 (65.1) Afterd Yes 598 (100) 244 (40.8) 354 (59.2) < 0.001 No 365 (100) 286 (78.4) 79 (21.6) Total 963 (100) 530 (55.0) 433 (45.0) a c² test. b History of first chemoprophylaxis. c Figures in parentheses are percentages. d History of second chemoprophylaxis. 833Bulletin of the World Health Organization | October 2006, 84 (10) Research Chemoprophylaxis and re-emergent P. vivax malaria in the Republic of Korea Changsoo Kim et al. Résumé Chimioprophylaxie et caractéristiques épidémiologiques du paludisme à P. vivax réémergent en République de Corée Objectif En République de Corée, les soldats stationnés dans des zones où ils étaient exposés à un risque de contracter le paludisme reçoivent une chimioprophylaxie antipalustre depuis 1997. Cependant, ce traitement peut faciliter le développement d’une pharmacorésistance et les accès primaires tardifs deviennent de plus en plus fréquents chez les individus l’ayant reçu. On a étudié les possibilités d’associations entre cette chimioprophylaxie d’une part et les caractéristiques épidémiologiques du paludisme à Plasmodium vivax réémergent et l’efficacité du traitement d’autre part en utilisant une base de données mondiale sur le paludisme. Méthodes Parmi les soldats exposés à un risque de paludisme entre 1999 et 2000, on a étudié tous les cas de paludisme à P. Vivax (1158) apparus avant le 31 décembre 2003. Les accès précoces et tardifs ont été définis respectivement comme les cas survenant dans un délai < 2 mois ou > 2 mois après le dernier jour d’exposition au risque de paludisme. Résultats Parmi ces cas, 634 (72,0 %) avaient reçu une chimioprophylaxie antipalustre et 324 (28,0 %) non. Les cas de paludisme sont apparus principalement en été, avec un pic en juillet-août. La stratification par antécédents de chimioprophylaxie a fait apparaître des différences dans les délais d’apparition. Une plus forte prévalence des accès précoces a été relevé dans le groupe n’ayant pas reçu de chimioprophylaxie, tandis que dans le groupe traité, la plupart des cas correspondaient à des accès primaires tardifs. Parmi ces derniers, 312 parmi 461 (67,7 %) ne prenaient pas régulièrement leur primaquine. Après le traitement du premier accès, 14 individus (1,2 %) parmi 1158 ont dû être retraités ; tous les cas retraités ont été guéris en utilisant la même posologie et le même schéma thérapeutique que pour le premier traitement. Conclusion En République de Corée, il existe une association entre l’augmentation des cas d’accès primaires de paludisme à P. Vivax réémergent et l’utilisation d’une chimioprophylaxie antipalustre. Resumen Quimioprofilaxis y epidemiología de la malaria reemergente por P. vivax en la República de Corea Objetivo En la República de Corea, los soldados emplazados en zonas con riesgo de malaria vienen recibiendo quimioprofilaxis antimalárica desde 1997. Sin embargo, la quimioprofilaxis puede facilitar la aparición de farmacorresistencia, y la observación de ataques primarios tardíos en personas que han recibido quimioprofilaxis es cada vez más frecuente. Investigamos la relación existente entre la quimioprofilaxis y las características epidemiológicas y la eficacia del tratamiento de la malaria reemergente por Plasmodium vivax, usando para ello una base de datos de ámbito nacional sobre la malaria. Métodos Entre los soldados expuestos al riesgo de contraer malaria entre 1999 y 2001, estudiamos todos los casos de malaria por P. vivax (1158) registrados antes del 31 de diciembre de 2003. Se definieron como ataques primarios tempranos o tardíos los casos ocurridos < 2 o > 2 meses después del último día de exposición al riesgo de malaria, respectivamente. Resultados De esos casos, 634 (72,0%) habían recibido quimioprofilaxis, y 324 (28,0%) no. Los casos se produjeron sobre todo en verano, con un máximo en julio/agosto. La estratificación en función de los antecedentes de quimioprofilaxis reveló distintos intervalos de incubación de la enfermedad. Los ataques primarios tempranos fueron más frecuentes en el grupo no sometido a quimioprofilaxis, mientras que en el grupo sometido a ella la mayoría de los casos fueron ataques primarios tardíos. De estos últimos, 312 de 461 (67,7%) no tomaban primaquina de forma regular. Tras el tratamiento del primer ataque, 14 (1,2%) de 1158 casos fueron tratados de nuevo; todos los casos retratados se curaron con las mismas dosis y pautas usadas en el primer tratamiento. Conclusiones En la República de Corea, el aumento de ataques primarios tardíos de malaria reemergente por P. vivax aparece asociado a la quimioprofilaxis antimalárica. صخلم ايروك ةيروهمج في ةطيشنلا تاروصتلما نع ةمجانلا ديدج نم ةثعبنلما ايرلاملل ةيئابولا صئاصخلاو ةيئايميكلا ةياقولا ىودعلا رطخ اهدوسي قطانم في نوركسعي نيذلا دونجلا ى َّقلتي :فدهلا لاإ ؛1997 ماع ذنم ايرلالما نم ةيئايميكلا ةياقولا ايروك ةيروهمج في ايرلالماب دايزلا يدؤي مام ةيودلأل ةمواقلما ثودح نم لهست دق ةيئايميكلا ةجلاعلما نأ .ةيئايميك ةياقو اوقلت نأ مهل قبس دارفأ ىدل ةرخأتم ةيئدب تماجه روهظ ةجلاعلما ةيلاعفبو ةيئابولا صئاصخلاب ةيئايميكلا ةياقولا قفارت انيصقتسا دقو نم ةدافتسلااب ،ةطيشنلا تاروصتلما نع ةمجانلا ديدج نم ةثعبنلما ايرلاملل .ايرلالما نع ةينطو تايطعم ةدعاق ةطيشنلا تاروصتلما نع ةمجانلا ايرلالما تلااح عيمج انضرعتسا :ةقيرطلا دونجلا فوفص ينب 2001و 1999 يـماع نـيب ةرـتفلا يـف تـثدح يتلا يـتلا تلااـحلا هذـه ددـع نأ اـندجوو ،اـيرلالماب ةباصلإا رطخل ينضَّرعلما .ةلاح 1158 غلب دق 2003 ماع نم برمسيد/لولأا نوناك 31 لـبق تـعقو نيرهش لبق عقت يتلا تلااحلا اهنأب ةركابلا ةيئدبلا تماجهلا تفِّرُع دقو تماجهلا تفِّرُع مايف ،ايرلالماب ةباصلإا رطخل ضرعتلل موي رخآ نم لقأ وأ موي رخآ نم نيرهش نم ثركأ دعب عقت يتلا تلااحلا اهنأب ةرخأتلما ةيئدبلا .ايرلالماب ةباصلإا رطخل ضرعتلل 634 ناـك ،ةـلاح 1158 اـهدادعت غـلب يتلا تلااحلا ينب نم :تادوجولما قلتت لم )%28( ةلاح 324و ،ةـيئايميك ةـياقو ىـ َّقلت دق )%72( ةـلاح اهاصقأ تغلبو ،فيصلا في تلااحلا مظعم تثدح دقو .ةيئايميك ةجلاعم لىإ ةيئايميكلا ةياقولا ةصق ليلحت ىدلو .سطسغأ/بآو ويلوي/زوتم ْيَرهش في ةيئدبلا تماجهلا تناكو .ةتوافتم تاقوأ في ناك اهب ءدبلا نأ ينبت تاقبط تناك مايف ،ةيئايميك ةياقو قلتت لم يتلا ةعومجلما ىدل ًاعويش ثركأ ةركابلا ؛ةرخأتلما ةيئدبلا تماجهلا نم ةيئايميكلا ةياقولا تقلت يتلا تلااحلا مظعم 461 ينب نم ةلاح 312 ناك ةرخأتلما ةيئدبلا تماجهلاب ينباصلما ءلاؤه نمو ةمجهلا ةجلاعم دعبو .مظتنم لكشب ينكايمبرلا اوقلتي لم )%67.7( ةلاح ءافش ققحتو )%1.2( ةلاح 1158 ينب نم ةلاح )14( ةجلاعم تديعأ لىولأا مظنلاو تاعرجلا سفن مادختساب اهتجلاعم تديعأ يتلا تلااحلا عيمج .لىولأا ةجلاعلما في تمدختسا يتلا ةيجلاعلا نم ةثعبنلما ايرلاملل ةرخأتلما ةيئدبلا تماجهلا في دايدزا كانه :جاتنتسلاا مادختساب قفارتو ،ايروك ةيروهمج في ةطيشنلا تاروصتلما نع ةمجانلا ديدج .ةيئايميكلا ةياقولا 834 Bulletin of the World Health Organization | October 2006, 84 (10) Research Chemoprophylaxis and re-emergent P. vivax malaria in the Republic of Korea Changsoo Kim et al. 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Cases of P. vivax malaria that occurred in soldiers and veterans of the Republic of Korea army after the start of the second round of chemoprophylaxis, stratified by history of chemoprophylaxis Chemoprophylaxis received No. of patients Latency period P-valuea First year Second year Early Late Yes Yes 443 (100)b 220 (49.7) 223 (50.3) < 0.001 No 113 (100) 113 (100.0) 0 (0.0) Total 556 (100) 333 (59.9) 223 (40.1) No Yes 155 (100) 24 (15.5) 131 (84.5) < 0.001 No 252 (100) 173 (68.7) 79 (31.3) Total 407 (100) 197 (48.4) 210 (51.6) a c² test. b Figures in parentheses are percentages.