TRANSACTIONS OFTHE ROYAL SOCIETY OFTROPICAL MEDICINE Severe and complicated malaria treated artemether in Viet Nam AND HYGIENE (1997) 91,465467 with artemisinin, artesunate 465 or Ha Vi&, Nguyen Ngoc Huon8, Tran Thi Bich Ha2, Bui Minh Cuongl, Nguyen Hoan Phu’, TranThi Hong Chaul, Phan Tan Quoi2, Keith Arnold3 and Tran Tinh Hien’ ‘Centre for Tropical Diseases, Cho Quan Hospital, 190 Ben Ham Tu, District 5, Ho Chi Minh City, Vz’etNam;2Tan Phu Hospital, Dong Nai Province, Viet Nam;3Roche Asian Research Foundation, Hong Kong Abstract One hundred and seventy five Viemamese adults with severe and complicated malaria admitted to a rural district hospital were entered into an open randomized comparative study to compare treatment regimens based on artemisinin and its derivatives.The median time of defervescence was 48 h (95% confident interval [CI] 38-58 h) in those given intramuscular (i.m.) artemether, 42 h (95% CI 36-48 h) in those given arternisinin suppositories, 36 h (95% CI 30-42 h) in those receiving artesunate (i.m.) and 30 h (95% CI 18-42 h) in those receiving intravenous artesunate (eO.13) The respective median parasite clearance times were 30 h (95% CI 26-34 h), 30 h (95% CI 24-36 h), 24 h (95% CI 15-33 h), and 24 h (95% CI 15-33 h) (-0.30); the median times for recovery of consciousness were 47 h (95% CI 31-63 h), 24 h (95% CI 18-30 h), 30 h (95% CI 18-42 h), and 24 h (95% CI 4-44 h) eO.18); and the mortality rates were l.l%, 17.6%, 10.2% and 16*6%, respectively eO.64) There was no significant difference in efficacy between the treatments Keywords: malaria, chemotherapy, artemether, artemisinin, artesunate,Viet Nam Introduction In recent years, artemisinin and its derivatives have been used widely in Viet Nam and other developing countries to treat uncomplicated malaria caused by Plasmodium falciparum They have also been used in severe and complicated malaria with good results (WHITE, 1994) Recent studies have compared individual preparations of artemisinin with quinine, but direct comparisons between all the artemisinin derivatives have not been made Consequently, it is not known which preparation and route of administration are preferable In 1992, we reported a study comparing artemisinin suppositories with intravenous (i.v.) artesunate and i.v quinine in the treatment of cerebral malaria However, there were few cases in the group treated with artemisinin suppositories, owing to discontinuation of the supply from the manufacturer (HIBN et al., 1992a) We also showed that intramuscular (i.m.) artesunate and i.v artesunate were equally efficacious (HIEN et al., 1992b) We conducted &e present study to compare the efflcacv of different retimens of artemisinin and its derivative; in the treatment of severe and complicated malaria caused by I? falciparum in a rural hospital setting Patients and Methods The study was an open randomized comparative study, conducted between 1992 and 1994 in Tan Phu regional hospital, which is responsible for health care in districts, Tan Phu and Dinh Quan, in the rural area of Dong Nai province, southern Viet Nam In this region, malaria is endemic throughout the year and the major employment is rice farming and forestry Inclusion criteria The patients were recruited into the study if 15 years of age or older, of either sex, with clinical symptoms and signs of malaria and the presence of asexual form of I? falciparum in their peripheral blood In addition, they must have had at least one of the following signs: (i) unrousable coma (Glasgow coma score Cll), (ii) hypoglycaemia (blood glucose ~2.2 mmol/L [40 mg%], (iii) acute renal failure (plasma creatinine >265.2 pal/L [3 mg%] with or without Address for correspondence: Tran Tinh Hien, Centre for Tropical Diseases, Cho Quan Hospital, 190 Ben Ham Tu, District 5, Ho Chi Minh City, Viet Nam; phone +84 8353804, fax +84 8353904 oliguria), (iv) jaundice (total bilirubin >51.3 mol/L [3mg%]) with parasitaemia > lOOOOO/~ or with plasma creatinine >1=5 mg%, (v) anaemia (haematocrit lOOOOO/pL, (vi) shock (systolic arterial pressure ~80 mmHg with a thready pulse and cold clammy extremities), and (vii) hyperparasitaemia >5OOOOO/pL(HIEN et al., 1996) Exclusion criteria Patients were excluded from the study if prior treatment with more than g of quinine or doses of artemisinin or a derivative had been recorded by the peripheral health care worker Pregnant patients in the first trimester, and patients with concomitant diseases (active tuberculosis, bacterial meningitis, etc.), or mixed infections with l? vivax were also excluded from the study Ethics Informed consent for participation was obtained from the patients or their relatives (in the case of comatose patients) The study was approved by the Scientific and Ethical Committee of the Centre for Tropical Diseases, Ho Chi Minh City, Viet Nam Clinical procedures On enrolment, a thorough history was taken and clinical examination made, and the details were recorded on a standard forni Peripheral blood films were prepared for parasite counts every h, until consecutive films had failed to reveal parasites Blood was also taken for a complete blood count and routine biochemistry (blood glucose, serum creatinine, serum bilirubin) The decree of parasitaemia was determined as the nm’nber of p&asitized red blood cells uer 1000 red blood cells (thin film) or the number 03 parasites per 400 leucocs& (thick film) Axillary temperature, pulse, arterial blood pressure, respiratory rate, and Glasgow coma score were recorded every h Treatment regimens When a patient fulfilled the enrolment criteria, a sealed envelope containing the code for the treatment regimen was opened to allocate him/her to one of the following treatment groups (i) Artemether (Kunming Pharmaceutical Factory, Yunnan, People’s Republic of China), i.m.: 200 mg initiallv, then 100 ma at 24 48 and 72 h (iij Artemisinin-suppo&tories (Viet Nam Industrial Development of Pharmaceutics, Ho Chi Minh City, 466 HAVINH ETAL Viet Nam): 1200 mg initially, then 400 mg at 4, 24, 48 and 72 h The same dosage of artemisinin was readministered if the sunnosit&es were excelled within h of insertion -(iii1 Artesunate (Guilin No Pharmaceutical Factory,‘G&angxi, Peopie’s Republic of China), i.m.: 120 mg initially, then 60 mg at 24, 48 and 72 h (iv) Artesunate, i.v.: 120 mg initially, then 60 mg at 24,48 and 72 h All patients received 750 mg mefloquine (Lariam@, Roche) as a single dose after regaining consciousness or at day Fluid and electrolyte replacement, antipyretics, and other ancillary treatment were given when needed, as guided by the World Health Organization (WHO), 1990) Patients with acute renal failure requiring dialysis were transferred to the Centre for Tropical Diseases in Ho Chi Minh City for peritoneal dialysis We allocated the first 120 cases randomly to the treatment groups When 30 patients had been recruited to the i.v artesunate group, we stopped recruitment of patients into this group and randomly allocated the next 60 cases to the remaining groups sons were enrolled Five patients were excluded from the analysis (one each in the i.m and i.v artesunate groups, in the i.m artemether group, and one in the artemisinin suppository group) because a review of admission blood films showed that their parasite counts were below 5OOOOO/pL and there was no additional criterion of severity Therefore, 175 patients, 45 in the i.m artemetber group, 51 in the artemisinin suppositories group, 49 in the i.m artesunate group and 30 in the i.v artesunate group, were included in the analysis There was no significant difference in any of the major admission clinical and laboratory characteristics of patients between the treatment groups (Table 1) Mortality The overall mortality rate was 13.7% (24 cases) and it was similar in each erou~: 10.2% (5 cases) in the i.m artesunate group, 11.h (5; cases) in-the i.m: artemether group, 16.6% (5 cases) in the i.v artesunate group, 17.6% (9 cases) in those receiving artemisinin suppositories (x2= 1.66, -0.64) Post-mortem examination was unavailable and so the exact causes of death could not be established Assessment of results We assessed fever clearance time (time for axillary temperature to fall to, and remain for 224 h at, 375°C or lower), parasite clearance time, time to regain full consciousness (in comatose cases), and fatality rate Recovery The fever clearance times, parasite clearance times, and times to regain full consciousness (in comatose cases) are presented in Table The differences between the groups were not significant There was no neurological sequel among those who recovered from a comatose state Statistical analysis The Kruskal-Wallis test was used to compare continuous variables, the x2 test for categorical variables, the Kaplan-Meier procedure with log rank tests for survival analysis of fever clearance time, parasite clearance time, and time to recovery of consciousness EpiInfo version 6.0 and SPSS for WindowsTM version 6.0 packages were used All values of P