Severe and complicated malaria treated with artemisinin, artesunate or 465 Ha Vi&, Nguyen Ngoc Huon8, Tran Thi Bich Ha2, Bui Minh Cuongl, Nguyen Hoan Phu’, TranThi Hong Chaul, Phan Tan
Trang 1Severe and complicated malaria treated with artemisinin, artesunate or
465
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’et Nam;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 4 treatment regi- mens 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 mor- tality rates were 1 l.l%, 17.6%, 10.2% and 16*6%, respectively eO.64) There was no significant difference in efficacy between the 4 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 individ-
ual 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 pref-
erable In 1992, we reported a study comparing artem-
isinin 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 set-
ting
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
2 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 Trop-
ical Diseases, Cho Quan Hospital, 190 Ben Ham Tu, District
5, Ho Chi Minh City, Viet Nam; phone +84 8 8353804, fax
oliguria), (iv) jaundice (total bilirubin >51.3 mol/L [3mg%]) with parasitaemia > lOOOOO/~ or with plasma creatinine >1=5 mg%, (v) anaemia (haematocrit <20%) with parasitaemia >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 treat- ment with more than 3 g of quinine or 2 doses of artem- isinin 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 clin- ical examination made, and the details were recorded on
a standard forni Peripheral blood films were prepared for parasite counts every 6 h, until 3 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&a- sitized 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 6 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 4 treatment groups
(i) Artemether (Kunming Pharmaceutical Factory, Yunnan, People’s Republic of China), i.m.: 200 mg in- itiallv, then 100 ma at 24 48 and 72 h
(iij Artemisinin-suppo&tories (Viet Nam Industrial Development of Pharmaceutics, Ho Chi Minh City,
Trang 2466 HAVINH ETAL
Viet Nam): 1200 mg initially, then 400 mg at 4, 24, 48
and 72 h The same dosage of artemisinin was re-
administered if the sunnosit&es were excelled within 2
- -
h of insertion
(iii1 Artesunate (Guilin No 2 Pharmaceutical Facto-
ry,‘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 4 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 dialy-
sis 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 treat-
ment groups When 30 patients had been recruited to
the i.v artesunate group, we stopped recruitment of pa-
tients into this group and randomly allocated the next
60 cases to the remaining 3 groups
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
Statistical analysis
The Kruskal-Wallis test was used to compare contin-
uous 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<O.O5 were considered significant
Results
Between March 1992 and September 1994, 180 per-
sons were enrolled Five patients were excluded from the analysis (one each in the i.m and i.v artesunate groups, 2 in the i.m artemether group, and one in the artemisinin suppository group) because a review of ad- mission blood films showed that their parasite counts were below 5OOOOO/pL and there was no additional cri- terion 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 admis- sion clinical and laboratory characteristics of patients between the 4 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 supposi- tories (x2= 1.66, -0.64) Post-mortem examination was unavailable and so the exact causes of death could not be established
Recovery The fever clearance times, parasite clearance times, and times to regain full consciousness (in comatose cas- es) are presented in Table 2 The differences between the 4 groups were not significant There was no neuro- logical sequel among those who recovered from a com- atose state
Discussion Since 1979, research in China has shown good results after the treatment of uncomplicated and severe and complicated malaria with artemisinin and its derivatives (Lr et al., 1994) Following these initial results, many other comparative studies (including double-‘blind’ studies) have shown that both artestunate and artemeth-
er can lower the fatality rate in severe and complicated Table 1 Admission clinical and paraclinical characteristics of the four treatment groups
Artemether
ifltI~lllUSCU1~~
Artemisinin suppositories intramuscular Artesunate intravenous Artesunate P”
Age (year+
Admission temperature (0C)b 28(1665) [22-371 28(16-62)[2141]
Haematocrit (%)b 38(37415) [37.5-391 38 (3740.6) [37-391
White blood cell count (x109@ 7500(420&19000) 34(1145) [25-381 31.5(10-57)[26-381 7500(5000-25300)
[7000-90001 [6700-82001 Parasitaemia (/pL)c 20179(140-1044000) 34538(40-1065000)
[2000-1519761 [18212-2863681
No of patients with complication&
Cerebral malaria
Anaemia
Jaundice
Hyperparasitaemia
Acute renal failure
Hypoglycaemia
Shock
3
BKruskal-Wallis test
bMedian values (range in parentheses) [interquartile range in brackets]
CGeometric mean (range in parentheses) [interquartile range in brackets]
dSome patients had more than one complication
Table 2 Results of treatmenE
24 (15-66) [la-391 30 (15-60) [22-371 0.7
38 (3741) [37.5-38.51 38 (3741) r36.5401 0.9 30.5(1548) [24,5-361 32( 16-42) [26-361 0.8 7500(2000-14400) 7000(4100-10500) 0.8 [6500-85501 [6800-80001
33174(60-1751000) 17159(20-1217000) 0.5 [3893-2447941 [1520-3647421
6
3
4
0
4
1
1
0
Artemether Artemisinin Artesunate Artesunate intramuscular suppositories intramuscular intravenous rb
aAll values are medians (95% confidence intervals in parentheses), except for fatality rates
bLog rank test, except for fatality rate (x2)
Trang 3467
malaria (HIEN et al., 1992a; WIN et al., 1992; KAR-
BWANG et al., 1995) However, recent large randomized
studies have not shown significant differences in mortal-
ity and there is no consensus about the best drug and the
best route of administration (WHITE, 1994) We believe
that this is the first randomized study directly to com-
pare artemisinin (in suppositories) with its derivatives,
artesunate and artemether, in the treatment of severe
and complicated malaria in a rural hospital
The difference in mortality rates between the 4
groups was not significant Nevertheless, any conclusion
about the mortality rates should be circumspect because
the power to detect a difference between these case mor-
tality rates was quite low (8.4-l 1.1%) due to the rela-
tively small number of patients However, the rates
were, in general, similar to those reported in Mvanmar
(14% for-i.m artemether and 8.3% for i.v artesunate)
(WIN et al., 1992) and in Thailand (12.8% for i.m arte-
mether) (k4RBW~ANG et cd., 1995)
The longest time to recovery of consciousness in our
trial was in the artemether group (although the differ-
ence was not statistically significant), and this is con-
cordant with the result of a recent study in which a
prolonged coma period was also reported in patients
treated with i.m artemether (median 66 h compared
with 48 h in patients receiving i:m quinine) (mENit al.,
1996) The reason for this orolonaed coma in natients
treated with i.m artemethei is unknown, but an acute
reversible drug effect cannot be excluded (HIEN et al.,
1996) A larger study is needed to compare i.m arte-
mether with i.m artesunate
The results of the present study substantiate our pre-
vious report that artemisinin suppositories can be used
to treat severe and complicated malaria with efficiency
equal to that of i.v artesunate (HIEN et al., 1992a) Ar-
temisinin suppositories, unlike artesunate or artemether
given by injection, are simple to administer, easy to
store, and can be produced locally in Viet Nam Artem-
isinin suppositories have been used successfully to treat
uncomplicated falciparum malaria in adults (ARNOLD et
al., 1990) and children (HIEN et al., 1991), and have
also been shown to reduce the mortality of cerebral ma-
laria (HIEN et al., 1992a) For the best outcome, treat-
ment of severe and complicated malaria should be
started as soon as possible In Viet Nam, the district
hospitals serve as an intermediate level of medical care
between the village health centres and provincial or ter-
tiary hospitals; they receive patients transferred from vil-
lage health centres or directly from neighbouring
households Therefore the district hosnitals are the ideal
setting for early treatment of severeSand complicated
malaria Artemisinin suppositories may, therefore, be
useful at the peripheral level of the health care system in
many tropical areas where malaria is endemic and re-
sources are limited
Conclusions
The results of this study suggest that artemisinin sup-
positories, i.m artemether, and artesunate (either i.m
or i.v.) can be used to treat severe and complicated ma-
laria caused by I? falcipurum with good results Howev-
er, artemisinin suppositories, which are easy to
administer, do not require special treatment equipment,
and can be stored at room temperature, may be appro- priate for the treatment of severe and complicated ma- laria in primary health care facilities throughout the developing world
Acknowledgements
We thank the doctors and nurses of Tan Phu Hospital and the Malaria Research Unit of the Centre for Tronical Diseases,
Ho Chi Minh City, for their valuable help in this study, MS Ju- lie Simpson for statistical advice, and Dr Jeremy Farrar and Professor Nicholas J White for reviewing the manuscript This study was funded by the Roche Asian Research Foundation, Hong Kong
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