Response of falciparum malaria to different antimalarials in Myanmar.

Response of falciparum malaria to different antimalarials in Myanmar M. N. Ejov, 1 T. Tun, 2 S. Aung, 3 & K. Sein 4 The purpose of the study was to ascertain the therapeutic efficacy of different treatments for uncomplicated falciparum malaria in the hospitals in Sagaing, northern and eastern Shan, to facilitate updating the existing national antimalarial drug policy. The proposed 14-day trial for monitoring the efficacy of treatments of uncomplicated falciparummalaria is an efficient method for identifying treatment failure patterns at the intermediate level (township hospital) in the Union of Myanmar. Minimal clinical and parasitological data for days 0±14 were required to classify treatment failure and success. Clinical and parasitological responses on day 3 and days 4±14 were used as clear examples of early and late treatment failure, respectively. Mefloquine is five times more likely to be effective than chloroquine and sulfadoxine- pyrimethamine (S-P), whereas chloroquine and S-P treatments have nearly identical failure patterns. The alarming frequency of clinical and parasitological failure (failure rate >50%) following chloroquine treatment was reported in Sagaing and following S-P treatment in Sagaing and eastern Shan. Voir page 247 le re sume en francËais. En la pa gina 248 figura un resumen en espanÄ ol. Introduction Malaria is still a major health problem in Myanmar. Resistance of Plasmodium falciparum to antimalarial drugs is a major contributing factor to the deteriora- tion ofmalaria control. Chloroquine and sulfadoxine- pyrimethamine (S-P) resistance at various levels is now common throughout the country (1, 2). Resistance to mefloquine is still limited to the Thai±Myanmar border, but there is some concern that the problem may assume larger dimensions in the near future (3). In the face of increasing resistance of P. falciparum to most antimalarial drugs, monitoring drug efficacy may facilitate decision-making about the use of antimalarials for treatment of uncompli- cated falciparum malaria (4). The purpose of this study was to ascertain the therapeutic efficacy of treatment of uncomplicated falciparum malaria in the hospitals in Sagaing Division and Shan State with a view to updating the existing national antimalarial drug policy. Materials and methods Study area The study was carried out in the township hospitals of Katha (Sagaing Division), Hsipaw (northern part of Shan State), and Tachileik (eastern part of Shan State). The study area is characterized by endemic and seasonal forest-related malaria; Anopheles minimus and A. dirus are the principal vectors. The most prevalent parasite species is P. falciparum. Resistance to chloroquine and S-P at various levels is widespread in these areas. Mefloquine resistance is reported in Tachileik township, which is situated on the Thai± Myanmar border. In these townships, malaria mortality and morbidity rates reported in 1994 ranged from 21.9 to 65.8 per 100 000 population, and from 17.0 to 85.3 per 1000 population, respectively. Study design A total of 118 patients with acute uncomplicated falciparummalaria were recruited into the study. The patients were randomly assigned to receive the oral therapeutic regimens described below. A history of previous use of any antimalarial drugs was not a criterion for exclusion. However, patients with clinical symptoms compatible with severe or complicated malaria or with any other symptoms or signs of nonmalarial etiology were excluded from the study and referred to appropriate health services. Patients who developed severe or complicated malaria during the trial were also excluded from the study. Blood samples were taken to detect malaria parasites and to measure haemoglobin. Thick-blood smears were Giemsa-stained. The number of para- sites per 200 leukocytes was multiplied by 40 to give the count per ml 1 Chief Technical Expert, UNDP/WHO Malaria Control Project, WHO Country Representative's Office, 39, Shwe Taung Gyar Road, P.O. Box 14, Yangon, Myanmar. Requests for reprints should be sent to this author. 2 Assistant Deputy Director, VBDC, Department of Health, Yangon, Myanmar. 3 Director, Disease Control, Department of Health, Yangon, Myanmar. 4 National Project Coordinator, UNDP/WHO Malaria Control Project, Office of WHO, Yangon, Myanmar. Reprint No. 5768 244 # World Health Organization 1999 Bulletin of the World Health Organization, 1999, 77 (3) Research The standard trials lasted for 14 days following the start of treatment under supervision. Drug regimens recommended were assigned by weight. There were three groups of patients and three different drug regimens: ± Group 1: chloroquine, 10 mg/kg on day 0 and day 1, and 5 mg/kg on day 2; ± Group 2: single dose of S-P, 25 mg/kg sulfa- doxine plus 1.25 mg/kg pyrimethamine (Fansi- dar); and ± Group 3: single dose of mefloquine, 15 mg/kg (Lariam, Hoffmann-La Roche, Basel, Switzerland). Patients showing clinical failure following chlor- oquine and S-P treatment received a single dose of S-P or a single dose of mefloquine, respectively. Patients showing clinical failure following mefloquine treat- ment received a dose of artesunate (Guilin Factory, Guangxi, China) at 2 mg/kg per day for 5 days. At enrolment (day 0), study subjects' parasite density, body temperature and haemoglobin level were recorded along with any other symptoms and signs. Follow-up examinations were scheduled on days 3, 7, and 14 after the start of treatment. Body temperature and parasite density were measured on each of these days, and the ratio of the parasite density on day 3 to that on day 0 was calculated. Haemoglobin levels were measured again on day 14. In addition, subjects could return at any time if their condition worsened, and body temperature and parasite density were measured at each unscheduled visit. If at any of the follow-up visits patients were febrile (temperature >37.5 o C) and parasitaemic, and no other causes of fever were found, alternative malaria treatment was given, and the case was classified as a treatment failure. The cases were classified as described below. Clinical and parasitological response Early treatment failure. Subjects presenting with persistent fever who were positive on day 3 (parasite density >25% of density on day 0), as well as those whose condition had worsened before day 3. Late treatment failure. Subjects whose fever initially cleared (temperature <37.5 o C) and were negative or positive on day 3 (parasite density425% of density on day 0) but who showed fever or parasitaemia on any day from day 4 to day 14. Treatment success. Afebrile subjects who were negative on day 3 and thereafter (early recovery), or subjects with or without fever and positive on day 3 (parasite density 425% of density on day 0) and negative thereafter (late recovery). Haematological effects of the different treat- ment regimens were assessed and compared. Statistical analysis Data were analysed using the statistical package Epi Info 6. Proportions were compared using w 2 and Fisher's exact tests. Rate ratios (RR) and Taylor series 95% confidence limits were also calculated (5). Results A total of 127 children and adult patients aged 1±58 years with acute uncomplicated falciparum malaria were selected for the study. Acute uncomplicated falciparum malaria was defined as an asexual parasitaemia between a minimum of 250 parasites/ ll and a maximum of 10 400 parasites/ml and fever (temperature >37.5 o C) or history of fever within the previous 48 h. Nine patients (7%) did not complete follow-up. Clinical data and baseline laboratory investigations on admission (Table 1) were compared for the chloroquine, S-P, and mefloquine groups. There were no significant differences between the three groups, except for the geometric mean parasitaemia: in both children and adult patients, P < 0.001. Clinical and parasitological response Group 1 (chloroquine). Of 41 patients, 2 (5%) did not complete follow-up; both patients were lost to follow-up on day 3. Of 39 patients who completed follow-up, 26 (66.6%) showed good response to treatment, and their cases were classified as treatment successes. A total of 13 (33%) patients were classified as treatment failures: 6 late treatment failures and 7 early treatment failures (Table 2). Among the patients classified as late treatment failures, 2 tested positive on day 3 (density <10% of density on day 0) and on day 7 (parasite density greater than that recorded on day 0). The other 4 patients became febrile and parasitaemic again on day 14 subsequent to clinical and parasitological remis- sion on days 3±14. Table 1: Baseline data for the study patients on admission Chloroquine S-P Mefloquine (Group 1) (Group 2) (Group 3) Children (<15 years of age) No. of patients 16 15 21 Mean age (years) 8 (3±14) a 7 (1±14) 9 (3±14) Mean weight (kg) 26 (11±41) 29 (9±54) 25 (12±48) Mean temperature ( o C) 38.3(37.5±38.9) 38.5(37.5±39.1) 38.5(37.5±39.4) Mean haemoglobin level ‹ SD (g/dl) 8.8 ‹ 2.0 9.4 ‹ 1.3 9.8 ‹ 1.3 Geometric mean parasitaemia (per ml) 2 855 5 256 5 639 Adult patients (>15 years of age) No. of patients 23 19 24 Mean age (year) 27(15±48) 28(15±58) 25(15±42) Mean weight (kg) 52.5(33.5±70) 58(44.5±68) 54.5(33±76) Mean temperature ( o C) 38.6(37.5±39.5) 38.6(37.5±39.9) 38.9(37.5±41.1) Mean haemoglobin level ‹ SD (g/dl) 10.5 ‹ 1.9 9.8 ‹ 1.9 9.8 ‹ 1.9 Geometric mean parasitaemia (per ml) 5 876 4 793 6 955 a Figures in parentheses are the range. 245Bulletin of the World Health Organization, 1999, 77 (3) Response of falciparum malaria to different antimalarials in Myanmar Among the patients classified as early treat- ment failures, 3 patients tested positive on days 2±3, with a parasite density greater than that recorded on day 0; the other 4 patients also tested positive on days 2±3, with a density greater than 50% of that recorded on day 0. Group 2 (S-P). Of 37 patients, 3 (8%) did not complete follow-up; 1 was lost to follow-up on day 7, and two patients were lost to follow-up on day 14. Of 34 patients who completed follow-up, 22 (64.7%) showed good response to treatment, with clinical and parasitological cure on or before day 3. Twelve (35.3%) cases were classified as treatment failures: 5 as late treatment failures and the other 7 as early treatment failures (Table 2). The 3 cases of successful treatment (late recovery) had a density on day 3 that was less than 10% of the density recorded on day 0 and became negative thereafter. Late treatment failure cases following clinical and parasitological remission on day 3 became positive on days 7 or 14 except for one case of parasitaemia on day 3with a parasite density <10%of that recorded on day 0. The 4 patients showing fever and parasitaemia on day 7 had a density 450% of that recorded on day 0, whereas the patient negative for fever and parasitaemia on day 7 became positive on day 14, with a density greater than that recorded on day 0. The 7 patients classified as early treatment failures had a parasite density on day 3 greater than 30% of that on day 0. Group 3 (mefloquine). Of 49 patients, 4 (8%) did not complete follow-up; 1 was lost to follow-up on day 3 and the remainder on day 14. Of 45 patients who completed follow-up, 42 (93.3%) showed good response to treatment, and their cases were classified as treatment successes. Four patients were still parasitaemic on day 3 with a parasite density <15% of that on day 0, but became negative thereafter and were classified as late recovery treatment successes. The remaining 3 patients were treatment failures: 1 late treatment failure and 2 early treatment failures (Table 2). Patients classified as early treatment failures had a density on day 3 greater than 50% of that on day 0, whereas the patient classified as a late failure became febrile and parasitaemic only on day 14. The highest proportion of treatment failures was observed for chloroquine (50.0%) in Katha, and for S-P (62.5%) and mefloquine (22.2%) in Tachileik (Table 2). Mefloquine was 5.29 times and 5.00 times more likely to be effective than S-P and chloroquine, respectively, and there was strong evidence of the difference between mefloquine and S-P treatments (RR = 5.29; 95% CI, 1.62±17.30; P < 0.01) as well as between mefloquine and chloroquine (RR = 5.00; 95%CI, 1.54±16.27; P< 0.01). In contrast, there was no difference in the therapeutic efficacy of chloro- quine and S-P (RR = 0.94; 95% CI, 0.50±1.78; P >0.1). Some of the treatment successes and failures following chloroquine, S-P, and mefloquine treat- ment were compared (Table 2 and Fig. 1). Results show no significant differences between drug regi- mens in each area or between different areas for the same drug regimen (P > 0.05, Fisher's exact test). There was no significant difference in mean haemoglobin levels on days 0 and 14 in children and adult patients for any of the antimalarial drug regimens (P > 0.1). Discussion The proposed 14-day trial to monitor the efficacy of antimalarial treatment of uncomplicated falciparum malaria is an efficient method for identifying patterns of clinical and parasitological failure at the inter- mediate level (township hospital) in Myanmar. Minimal clinical and parasitological data on days 0±14 were required to classify treatment failure and success. Clinical and parasitological responses on day 3 and days 4±14 were used to clearly define early and late treatment failures, respectively. These results show that mefloquine was 5 times more likely to be effective in treatment of uncomplicated malaria than chloroquine and S-P, whereas chloroquine and S-P treatments have nearly identical failure patterns. The present study confirms previous findings from Myanmar (3) on the super- Table 2: Clinical and parasitological response of uncomplicated falciparum malaria to different antimalarial drug regimens in the hospitals in Sagaing Division and Shan State No. in No. in Hsipaw, No. in Tachileik, Total Katha, northern eastern Sagaign Shan Shan Chloroquine Early treatment failures 4 (28.6) a 2 (14.3) 2 (16.7) 7 (18) Late treatment failures 3 (21.4) 2 (14.3) 1 (8.3) 6 (15.4) Treatment success 7 (50) 10 (71.4) 9 (75) 26 (66.6) Total 14 (100) 14 (100) 12 (100) 39 (100) S-P Early treatment failures 2 (25) 2 (11.1) 3 (37.5) 7 (20.6) Late treatment failures 2 (25) 1 (5.6) 2 (25) 5 (14.7) Treatment success 4 (50) 15 (83.3) 3 (37.5) 22 (64.7) Total 8 (100) 18 (100) 8 (100) 34 (100) Mefloquine Early treatment failures 1 (9.1) 0 (0) 1 (11.1) 2 (4.4) Late treatment failures 0 (0) 0 (0) 1 (11.1) 1 (2.2) Treatment success 10 (25) 25 (100) 7 (77.8) 42 (93.4) Total 11 (25) 25 (100) 9 (100) 45 (100) a Figures in parentheses are percentages. 246 Bulletin of the World Health Organization, 1999, 77 (3) Research iority of mefloquine over chloroquine and S-P throughout the country. Although statistically significant differences between areas were not found, there may be strong grounds for believing pressure to use one drug or another varies according to geographical area. Despite the superiority of mefloquine in all the study areas, its efficacy is steadily declining in eastern Shan (cure rate, 77.8%) and even in Sagaing (cure rate, 90.9%). However, the drug response profile in Myanmar is still much more satisfactory than that in Thailand (6,7). For S-P, the highest proportion of treatment failures was recorded in eastern Shan (62.5%) and the lowest (16.7%) in northern Shan. In contrast, the highest proportion of failures following chloroquine treatment was recorded in Sagaing (50%) and the lowest (25%) in eastern Shan. These findings contrast with the situation in Thailand, where P. falciparum has been highly resistant to chloroquine and S-P since the mid-1970s to early 1980s. The frequency of clinical and parasitological failure following chloroquine treatment in Sagaing, and S-P treatment in eastern Shan and Sagaing, has reached an unacceptable level (failure rate >50%) and can no longer be considered as adequate therapy for uncomplicated falciparum malaria (Fig. 1). Given these results, a decision to change first-line (chloro- quine) and perhaps even second-line (S-P) treatment to mefloquine in Sagaing and eastern Shan might be appropriate, at least for nonimmune patients. Most probably, treatment failure patterns reflect trends in hospital-based mortality and severity of malaria. According to available data, malaria mortality rates have risen in eastern Shan and Sagaing in recent years. In contrast, rates have remained stable in northern Shan. The presence of a wide variety of antimalarials including artemisinin and its derivatives on the local market, uncontrolled provision of an array of malaria treatments by private practitioners, and the common practice of self- medication Ð all often at odds with the recommen- dations of national drug policyÐmakemanaging the disease extremely complicated in the public sector. Most patients with malaria presenting to health facilities at the intermediate and peripheral levels have been treated previously, and underdosing is frequent. The inadequacy of the drugs currently available, noncompliance, and delays in treatment usually result in ineffective treatment for malaria, contributing to an increase in the incidence of severe disease and death. Despite the small sample size, our results may be used as an important indicator of the variability of the therapeutic response of uncomplicated falciparum malaria to different antimalarial treat- ments in Myanmar. Additional drug efficacy assess- ments throughout the country are needed to support national antimalarial drug policy. n Acknowledgements This study was part of the UNDP-funded malaria control project carried out by WHO in Myanmar. We thank UNDP for the funding that made the work possible and are grateful for assistance given by the vector-borne disease control and the public health staff involved in the study. We especially thank Dr L. Molineaux, and Dr V. S. Orlov, who con- tributed their time and expertise to this work. Re sume Re ponse du paludisme aÁ falciparum non complique aÁ diffe rents traitements antipalude ens au Myanmar Au Myanmar, l'aggravation du probleÁme de la pharmaco- re sistance rend la prise de de cision de plus en plus difficile en matieÁ re de the rapeutique antipalustre. Notre e tude, qui s'est de roule e dans des hoà pitaux municipaux de la Division de Sagaing et de l'Etat de Shan, se propose d'e valuer l'efficacite the rapeutique de diffe rents traite- ments dans les cas de paludisme aÁ falciparum non complique , afin de faciliter la mise aÁ jour de la politique nationale dans le domaine des antipalude ens. L'essai de deux semaines que nous proposons pour controà ler l'efficacite the rapeutique du traitement d'un paludisme aÁ falciparum non complique est une me thode efficace pour mettre en e vidence, au niveau des municipalite s, un e chec the rapeutique sur le plan Fig. 1. Proportion of treatment failures (series 1) and success (series 2) following different drug regimens in Katha (A), Hsipaw (B), and Tachileik (C). 247Bulletin of the World Health Organization, 1999, 77 (3) Response of falciparum malaria to different antimalarials in Myanmar clinique ou parasitologique. Pour classer un traitement dans la cate gorie «e chec» ou «succeÁ s» il a fallu recueillir un minimum de donne es cliniques et parasitologiques sur les deux semaines d'observation. La re ponse clinique et parasitologique obtenue au troisieÁme, au quatrieÁme et au quatorzieÁme jour peut eà tre utilise e pour de finir sans ambiguõÈte un e chec the rapeutique pre coce ou tardif. D'apreÁ s nos re sultats, la me floquine a cinq fois plus de chances d'eà tre efficace contre un paludisme non complique que la chloroquine ou la sulfadoxine- pyrime thamine (S-P), tandis que la chloroquine et la S-P sont aÁ peu preÁ s aussi inefficaces l'une que l'autre. Les tests statistiques ne font pas vraiment ressortir de diffe rence entre les re gions, mais tout porte aÁ croire que la pression en faveur de l'usage de tel ou tel produit varie en fonction de la situation ge ographique. Malgre la supe riorite de la me floquine dans toutes les re gions, son efficacite est en diminution constante dans le Shan oriental et meÃme dans le Sagaing. En ce qui concerne la S-P, la proportion la plus e leve e d'e checs the rapeutiques a e te enregistre e dans le Shan oriental et la plus faible dans le Shan septentrional. En revanche, la proportion la plus e leve e de cas rebelles aÁ la chloroquine a e te observe e dans le Sagaing et la plus faible dans le Shan oriental. La fre quence des e checs cliniques et parasitolo- giques aÁ la suite d'un traitement par la chloroquine ou la S-P au Sagaing et par la S-P dans le Shan oriental a atteint un niveau inacceptable. Ces produits ne peuvent plus eà tre conside re s comme utilisables pour le traitement du paludisme aÁ falciparum non complique si l'on veut e viter une augmentation des cas graves de paludisme et de la mortalite qui peut en re sulter. Resumen Respuesta del paludismo falciparum sin complicaciones a distintos regõÂmenes de tratamiento farmacolo gico en Myanmar El agravamiento del problema de la farmacorresistencia en Myanmar plantea cada vez ma s dificultades para la toma de decisiones sobre la utilizacio n de los medicamentos antipalu dicos. En el presente estudio se determino la eficacia terape utica de diferentes trata- mientos del paludismo por P. falciparum sin complica- ciones en los hospitales municipales de la Divisio n de Sagaing y del Estado de Shan para facilitar la actualizacio n de la vigente polõÂtica farmace utica nacional contra el paludismo. El ensayo de 14 dõÂas propuesto para vigilar la eficacia del tratamiento del paludismo por P. falciparum sin complicaciones es un me todo eficiente para identificar las pautas del fracaso clõÂnico y parasitolo gico a nivel municipal. Se requirio un mõÂnimo de datos clõÂnicos y parasitolo gicos de los dõÂas 0 a 14 para establecer el e xito o fracaso del tratamiento. Se utilizaron las respuestas clõÂnicas y parasitolo gicas observadas el dõÂa 3 y entre los dõÂas 4 a 14 para definir con claridad los fracasos precoz y tardõÂo del tratamiento, respectiva- mente. Los resultados muestran que la probabilidad de tratar eficazmente el paludismo sin complicaciones es cinco veces mayor cuando se utiliza mefloquina que cuando se usa cloroquina o sulfadoxina-pirimetamina (S-P), mientras que los tratamientos con cloroquina y S-P fracasan con parecida frecuencia. Con independencia de las pruebas de significa- cio n, hay razones fundadas para pensar que la presio n a favor de uno u otro fa rmaco tiene efectos diferentes dentro de la zona del estudio. Pese a la superioridad de la mefloquina en todas las zonas, su eficacia esta descendiendo de forma constante en Shan oriental e incluso en Sagaing. En el caso de la S-P, la proporcio n ma s alta de fracasos terape uticos se registro en el Shan oriental, y la ma s baja en Shan septentrional. Por el contrario, la proporcio n ma s alta de fracasos con la cloroquina se registro en Sagaing y la ma s baja en Shan oriental. La frecuencia de fracasos clõÂnicos y parasitolo gicos del tratamiento con cloroquina y S-P en Sagaing y del tratamiento con S-P en Shan oriental ha alcanzado un nivel inaceptable. Si se desea evitar que aumente la incidencia del paludismo grave y de la mortalidad subsiguiente en esas zonas, esos tratamientos ya no pueden considerarse una terapia adecuada del paludis- mo por P. falciparum sin complicaciones. References 1. Country Report onMalaria Control Programme inMyanmar. Paper presented at: Intercountry Consultative Meeting of National Malaria Control Programme Managers, 1995, South-East Asia Regional Office, World Health Organization, New Delhi, India. 2. Franco Tin et al. Forest-related malaria in Myanmar. In: Sharma VP et al., eds. Forest malaria in Southern Asia: proceedings of an informal consultative meeting, 18±22 February 1991, New Delhi. New Delhi, WHO Regional Office for South-East Asia, 1991: 133±141. 3. Soe Aung et al. Updated situation of drug-resistant Plasmodium falciparum in border areas of Myanmar. In: Abstracts of the Myanmar Health Research Congress, December 1994. Yangon, 1994: 17. 4. Antimalarial drug policies: data requirements, treatment of uncomplicatedmalaria, andmanagement of malaria in pregnancy. Report of an Informal Consultation, 14±18 March 1994 (unpublished document WHO/MAL/94.1070). 5. Kahn HA et al. Statistical methods in epidemiology. Oxford, Oxford University Press, 1989. 6. Wernsdorfer WH et al. A symposium on containment of mefloquine-resistant falciparum malaria in Southeast Asia with special reference to border malaria. Southeast Asian journal of tropical medicine and public health, 1994, 25: 11±18. 248 Bulletin of the World Health Organization, 1999, 77 (3) Research 7. RooneyW et al. Development of multi-drug resistance in forest- related falciparum malaria. In: Sharma VP et al., eds. Forest malaria in Southeast Asia: proceedings of an informal consultative meeting, 18±22 February 1991, New Delhi. New Delhi, WHO Regional Office for South-East Asia, 1991: 227±234. 8. Harinasuta T et al. Chloroquine-resistant falciparum malaria in Thailand. Lancet, 1965, 2: 657±660. 9. Sucharit P et al. In vivo and in vitro studies of chloroquine resistant malaria in Thailand. Annals of tropical medicine and parasitology, 1977, 71: 401±405. 10. Hurwitz ES et al. Resistance of Plasmodium falciparum to sulfadoxine-pyrimethamine in a refugee camp in Thailand. Lancet, 1981, 1: 1068±1070. 249Bulletin of the World Health Organization, 1999, 77 (3) Response of falciparum malaria to different antimalarials in Myanmar