COMPARISON OF THE PARASITOLOGIC EFFICACY OF AMODIAQUINE AND
SULFADOXINE-PYRIMETHAMINE IN THE TREATMENT OF PLASMODIUM
FALCIPARUM MALARIA IN THE BUNGOMA DISTRICT OF WESTERN KENYA
C. J. VREUGDENHIL, F. Y. SCHEPER, S. R. HOOGSTRAATTE, M. SMOLDERS, S. GIKUNDA, F. G. COBELENS, AND
P. A. KAGER
Faculty of Medicine, and Department of Infectious Diseases, Tropical Medicine and AIDS, University of Amsterdam, Academic
Medical Center, Amsterdam, The Netherlands; Malaria Unit, African Medical and Research Foundation, Nairobi, Kenya
children from western Kenya with uncomplicated Plasmodium falciparum malaria. A non-blinded, randomized, 14-day
study was performed and parasitologic criteria were used. Of 310 patients included, 238 (77%) completed the study: 120
received AQ and 118 received SP. In those treated with AQ, there were sensitive (S) infections in 107 patients (89.2%,
95% confidence interval [CI] ? 82.2, 94.1%), RI resistance in 10 (8.3%, 95% CI ? 4.1, 14.8%), RII resistance in 1
(0.8%, 95% CI ? 0, 4.6%), and RIII resistance in 2 (1.7%, 95% CI ? 0.2, 5.9%). In those treated with SP, there were
S infections in 74 patients (62.7%, 95% CI ? 53.3, 71.4%), RI resistance in 21 (17.8%, 95% CI ? 11.4, 25.9%), RII
resistance in 11 (9.3%, 95% CI ? 4.7, 16.1%), and RIII resistance in 12 (10.2%, 95% CI ? 5.4, 17.1%). Resistance rates
were consistently higher in the SP-treated patients (P < 0.001). Resistance to SP in this area has reached such levels that
it should no longer be the first-line treatment. Alternative treatment, such as SP plus AQ combination treatment or
artemisinin combination treatment, is urgently needed.
The efficacy of amodiaquine (AQ) and sulfadoxine-pyrimethamine (SP) was assessed in 310 symptomatic
Malaria is one of the most important causes of morbidity
and mortality in Africa. It is estimated that 0.5−2.5 million
persons die due to malaria and that 300−500 million clinical
cases occur yearly.1Epidemiologic data suggest that malaria
mortality has increased since 1984 because of increasing chlo-
roquine (CQ) resistance of Plasmodium falciparum.2Several
east African countries have adopted sulfadoxine-pyri-
methamine (SP) as first-line treatment for uncomplicated P.
falciparum malaria instead of CQ.1It was feared that resis-
tance to SP would develop relatively quickly because of its
long elimination half-life,3and this did occur in Kenya4,5and
Tanzania,5–7as it had previously occurred in Thailand.8
In Kenya, resistance to CQ was first detected in non-
immune tourists in 1978 and in semi-immune Kenyans in 1982
(for references see Shretta and others9). In the 1990s, the
percentage of resistance increased to 85% in western Kenya.9
In 1998, SP replaced CQ for first-line treatment and amodi-
aquine (AQ) became the drug for second-line treatment.9
Early studies showed good results for SP treatment, but re-
sistance developed rather quickly, and in recent years cure
rates varying from 50% to 90% have been reported from
different endemic areas in Kenya.4,10–18A study of SP effi-
cacy conducted in 1999−2000 in Nairobi, a non-endemic area
where reinfections hardly ever occur, showed 65% sensitive
(S) infections, 27% with an RI response, and 8% with RII-III
responses.19In vitro results are consistent with these in vivo
data; increased resistance of parasites to SP or one of its
components was demonstrated in studies on the Kenyan
coast.20For AQ, variable results have been reported from
various countries.21In Kenya, where AQ was only introduced
as a second-line drug, efficacy varied from 65%4to 88%17,
even up to 97% (Cobelens FG, unpublished data),22but Keu-
ter and others, who used a relatively low dose (25 mg/kg) of
AQ, reported a high (67%) resistance rate.23Recent studies
with a dose of 30 mg/kg showed cure rates of 74% at 14 days
and only 54% at 28 days after correction by a polymerase
chain reaction (PCR) for reinfections in Kenya, but higher
cure rates in Senegal and Gabon at 28 days of 81% (not
corrected) and 85% (PCR corrected), respectively.23In
Uganda, parasitologic cure rates after the use of SP, AQ, and
the combination of SP plus AQ were 70−74%, 84%, and
90−99%, respectively.24,25High levels of SP resistance have
been reported in Tanzania.5–7,26The East African Network
for Monitoring Antimalarial Treatment, founded in 1998 and
now including Uganda, Kenya, Tanzania, Zanzibar, Rwanda,
and Burundi, recently published data on CQ, AQ, and SP
from many sentinel sites, which confirmed the high failure
rates of CQ, the emergence of SP resistance, and the still good
performance of AQ.5
As part of the continuous monitoring of drug resistance in
Kenya by the African Medical and Research Foundation
(AMREF) in Nairobi4,12we compared the efficacy of SP and
AQ in the treatment of uncomplicated P. falciparum malaria
in symptomatic children in the Bungoma District of western
Kenya, an area with intense malaria transmission. Previous
data on drug resistance/sensitivity from this area were not
MATERIALS AND METHODS
Study area. The study was conducted between April and
June (rainy season) 2000 in the Bungoma District of western
Kenya, an area of intense malaria transmission near Lake
Victoria. The study sites were the Bungoma District Hospital,
the Webuye Panpaper Clinic, and the Sirisia Health Center.
The study was reviewed and approved by the Institutional
Review Board of the Academic Medical Center (Amsterdam)
and the Review Board of the African Medical and Research
Patients and recruitment. Symptomatic outpatients 6−59
months of age with a positive blood smear were enrolled after
informed consent of their parents or guardians was obtained,
provided that they had an uncomplicated monoinfection with
P. falciparum. Inclusion criteria were a parasitemia between
2,000/mm3and 250,000/mm3, a body weight ? 5 kg, a history
of fever in the preceding 24 hours or an axillary temperature
? 37.5°C at presentation, an ability to drink, and residence
within a pre-determined perimeter from health center/
Am. J. Trop. Med. Hyg., 71(5), 2004, pp. 537–541
Copyright © 2004 by The American Society of Tropical Medicine and Hygiene
hospital. Exclusion criteria were vomiting two or more times
in the preceding 24 hours, one or more convulsions in the
preceding 24 hours, an inability to sit up or stand, a hemo-
globin level < 5 g/dL, and signs of severe malaria, other febrile
diseases, underlying disease (cardiac, renal, or hepatic), or a
history of allergic reactions to AQ, SP, or other sulfa com-
Randomization and treatment. Treatment efficacy of AQ
and SP was assessed in a 14-day, randomized, non-blinded,
clinical trial. Treatment allocation was done in an uncon-
cealed fashion by the researchers by taking the next number
from a randomization list (one for each center) that was pre-
pared by one of us (FGC) before the start of the study from
a random number table. Block randomization was applied to
safeguard balance in numbers (blocks of 10). The AQ group
received amodiaquine (Camoquin?, 200-mg tablets; Parke-
Davis, Detroit, MI), 10 mg/kg of body weight, given orally on
days 0, 1, and 2, the SP group received sulfadoxine/pyri-
methamine (Fansidar?, 500 mg of sulfadoxine and 25 mg of
pyrimethamine per tablet; Roche, Basel, Switzerland), 25 mg
of sulfadoxine/kg of body weight, given orally once on day 0.
Treatment was given under supervision and any dose vomited
within an hour was repeated. Patients who vomited more than
once were excluded from follow-up. Patients with a body tem-
perature (axillary) > 38°C were given paracetamol syrup in
accordance with local policy.
Patient follow-up. After recruitment (day 0), patients were
seen again on days 1, 2, 3, 7, and 14 and on any other day in
between if fever and/or other symptoms developed. On each
occasion the clinical status was assessed and a thick blood
smear was prepared to determine the asexual parasite den-
sity. The temperature was measured on days 0, 1, 2, and 3 and
whenever clinically indicated. Patients who did not return for
follow-up were visited at home.
Study endpoints were based on parasitologic response,27
which was up to then the procedure used in the monitoring by
the AMREF.4,17Grade III resistance (RIII) was a parasit-
emia on day 2 ? 25% of the initial (day 0) value. If no data
for day 2 were available, data for day 3 were used instead.
Grade II resistance (RII) was a parasitemia on day 7 in pa-
tients without grade III resistance. Grade I resistance (RI)
was a parasitemia on day 14 in patients without grade II or III
resistance. Sensitive (S) was no grade I, II, or III resistance.
Patients were withdrawn from the study if an endpoint was
reached and were then given rescue treatment. Rescue treat-
ment was parenteral quinine for all those with parasitologic
failure in the presence of fever and oral SP both after AQ and
after SP treatment for those without fever. This was according
to local practice where AQ and other antimalarial drugs were
not normally available.
Lost to evaluation includes those patients who were with-
drawn at a parent’s or guardian’s request, those who were
given antimalarial or antibiotic therapy outside the protocol,
or those who did not return for evaluation for unknown cause
and who could not be found at home. In addition, due to
misunderstandings regarding the study protocol, some pa-
tients were given rescue treatment without reaching a study
endpoint and they were not followed-up further. They are
categorized as protocol violations.
Laboratory methods. Blood was obtained by finger prick
for thin and thick blood smears. The slide was fixed and
stained using Field’s stain. Parasite density was calculated by
counting the number of asexual parasites per 200 leukocytes.
As many fields as necessary were examined to find either 200
leukocytes or 500 parasites. The parasitemia was calculated
on the assumption of a leukocyte count of 8,000/?L. Parasite
density was assessed from the thick smear. Thin blood smears
were reviewed for species identification. In Sirisia, the hemo-
globin concentration was measured with a photometer (Com-
pur 1000?; Bayer Diagnostics and Electronic Gmbh, Munich,
Germany) after mixing 20 ?L of finger prick blood with 5 mL
of Drabkin solution. In Webuye and Bungoma, hemoglobin
was assessed by the HemoCue? procedure (Hemocue Ltd.,
Derbyshire, United Kingdom).
Statistical methods and analysis. Data were recorded on
case record forms and entered twice in an automated data-
base (Epi-Info version 6.0; World Health Organization,
Geneva, Switzerland and Centers for Disease Control and
Prevention, Atlanta, GA). Analyses were performed using
STATA version 6.0 (Stata Corp. College Station, TX). The
analysis was restricted to patients for whom parasitologic data
were available on days 2, 7, and 14. If data were missing for
day 2 but available for day 3, the latter were used instead. To
assess potential bias by differential loss to follow-up between
the treatment groups, a worst-case analysis was done in which
all patients for whom parasitologic data were missing were
assumed to have been resistant. Resistance grades were allo-
cated such that patients who were lost to follow-up before
grade III resistance could be ascertained were classified as
RIII, the remaining patients who were lost to follow-up be-
fore grade II resistance could be ascertained were classified as
RII, and the remaining patients who were lost to follow-up
were classified as RI.
Exact binomial confidence intervals (CIs) were calculated.
For comparison of categorical variables, the chi-square test
with Yates’ continuity correction for 2 × 2 tables or the two-
sided Fisher’s exact test were used as appropriate. All tests
were done at a significance level of P ? 0.05.
After screening, 310 patients were included in the study
and randomized to one of the treatment groups. The groups
were comparable with respect to their baseline characteristics
(Table 1). One hundred fifty-six were randomized to receive
AQ and 154 to receive SP. The numbers of patients enrolled
who did not complete the study were similar in the two treat-
ment groups both as a whole and when stratified for the rea-
sons they were excluded after enrollment (Figure 1). Of 310
patients, 238 (77%) completed the study. One patient with an
RIII response to SP developed signs of severe malaria and
died; none of the other patients with RII or RIII response
developed signs of severe malaria.
Sensitive infections were present in 107 (89.2%) patients
treated with AQ, but in only 74 (62.7%) patients treated with
SP (P < 0.001). For all three grades, resistance rates were
higher in the SP group than in the AQ group (P < 0.001)
(Table 2). High-grade resistance (RII-III) was observed in 23
of 118 patients (19.5%) receiving SP versus 3 of 120 patients
(2.5%) receiving AQ (P < 0.001).
In the worst-case analysis, the proportion of sensitive in-
fections was again higher in the AQ group than in the SP
group: 68.6% (107 of 156) versus 48.0% (54 of 154; P < 0.001),
VREUGDENHIL AND OTHERS
and resistance rates were consistently lower across the three
resistance grades (P ? 0.003). In this analysis, high-grade
resistance (RII-III) occurred in 50 of 154 patients (32.5%)
receiving SP versus 33 of 156 patients (21.2%) receiving AQ
(P ? 0.025).
In Kenya, resistance to SP, the first-line treatment for ma-
laria, has reached high levels in many, but not all, areas.5This
study showed a low sensitivity rate of 62.7% (95% CI ? 53.3,
74.1%) for SP in the treatment of non-severe P. falciparum
malaria in children in a high-transmission area in western
Kenya. Sensitivity to AQ was good: 89.2% (95% CI ? 82.2,
94.1%). The sensitivity to either drug may have been overes-
timated by this primary analysis since some of the patients
who were lost to evaluation may in fact have been failures.
We therefore included a worst-case analysis, in which it was
assumed that all patients lost to evaluation had resistant para-
sites. This analysis thus provides the minimum sensitivity and
maximum resistance that is compatible with our data. For
sensitivity to AQ this was 68.6%, and for sensitivity to SP this
was 48.0%, which is a statistically significant difference. Over-
estimation of drug sensitivity by our primary analysis may
have occurred in patients who received parenteral treatment
outside the study protocol or who were withdrawn for reasons
not consistent with the study protocol (protocol violations).
Since both were more frequent in the SP group than in the
AQ group, this underestimation of sensitivity is likely to be
more pronounced for SP than for AQ. It has to be mentioned
that the 14-day follow-up period may also underestimate the
true (28-day) risk of treatment failure.
Grade III resistance to SP was approximately as high as
grade II resistance (10.2% and 9.3%, respectively; Table 2).
However, this may be an overestimation since SP is a rela-
tively slowly acting drug; patients may continue to clear par-
asitemia without further treatment, and may become cured,
as has been observed after treatment with CQ.28High-grade
resistance (RII-III) to SP was significantly more frequent
than that to AQ, both in the primary and in the worst-case
Several explanations can be made for the differences in
resistance to SP and AQ. First, SP has a long elimination half
life, while AQ is a pro-drug that produces metabolites with
shorter half-lives. Resistance will develop more quickly to
drugs with long elimination half life.3Second, SP is widely
available and taken mostly without a prescription, possibly in
inappropriate dosages.29Conversely, AQ is not widely avail-
able. It has to be taken on three consecutive days, has a bitter
taste, and has the side effects of itching and vomiting. These
are all reasons why it is probably used less often, although
formal studies on its distribution and the preferences of the
public are lacking.
Finally, co-trimoxazole is commonly used in Kenya for the
treatment of fever of unknown origin, for chest problems, and
bacterial infections. One component of this drug, sulfameth-
oxazole, is a sulfa-drug similar to sulfadoxine and the other
component, trimethoprim, is an analog of pyrimethamine.
There is evidence of cross-resistance between pyrimethamine
and trimethoprim,30as well as between sulfadoxine and sul-
famethoxazole.31Terlouw and others demonstrated that
treatment history (recent use of SP) and treatment dose (dos-
ing based on age, not on actual body weight) were important
determinants of SP efficacy,32but after increasing the dose in
their study area in western Kenya, the proportion of treat-
ment failures continued to increase.33They emphasize that
adequate doses must be given from the start of deployment of
an antimalarial drug in an area.33In our study, since dosing
was based on actual body weight, underdosing was not the
cause of the high failure rate.
Results of a randomized, non-blinded, comparative trial comparing
amodiaquine (AQ) and sulfadoxine-pyrimethamine (SP) in the
treatment of 238 children with uncomplicated Plasmodium falci-
parum malaria in the Bungoma District of Kenya*
AQ (n ? 120)SP (n ? 118)
Sensitive 107 (89.2%)
Grade I resistance (RI)
Grade II resistance (RII)
Grade III resistance (RIII)
* Values in brackets are 95% confidence intervals.
versus sulfadoxine-pyrimethamine (SP) in the treatment of children
with uncomplicated Plasmodium falciparum malaria in the Bungoma
district of Kenya.
Profile of a comparative trial of amodiaquine (AQ)
Baseline characteristics of treatment groups in a multicenter study of
children with uncomplicated Plasmodium falciparum malaria in the
Bungoma District, of Kenya, 2000*
Treatment groupAQ (n ? 156)SP (n ? 154)
Age (months), mean (SD)
Weight (kg), mean (SD)
Parasitemia on day 0 (/mm3),
Temperature on day 0
(°C, axillary), mean (SD)
Fever on day 0
? 37.5°C, axillary
Hb (g/dL), mean (SD)
38.0 (1.0)38.1 (1.1)
9.3 (n ? 150)
8.9 (n ? 153)
* AQ ? amodiaquine; SP ? sulfadoxine-pyrimethamine; Hb ? hemoglobin.
AQ AND SP FOR THE TREATMENT OF P. FALCIPARUM MALARIA
Combining drugs with different modes of action and
mechanism of resistance is advocated to improve efficacy and
delay development and spread of resistance.1Combinations
with an artemisinin drug are preferred1and have also been
studied in Africa.34These artemisinin-based combinations
are not yet available everywhere on a large scale and are
more expensive than monotherapy and other combinations
such as SP-CQ or SP-AQ. A Cochrane analysis of combina-
tion treatments of SP-CQ and SP-AQ showed superiority of
the combination in comparison with monotherapy with re-
gard to sustained parasite clearance and clinical improve-
In Uganda, the current first-line treatment is SP-CQ5based
on studies comparing SP, AQ, and combinations of SP with
CQ or AQ.24,25Conversely, Rwanda opted for SP-AQ5
among other combinations, based on a study comparing AQ,
SP-AQ, and SP-artesunate.36In Kenya, the first-line treat-
ment is still SP, but in some areas such as the Bungoma Dis-
trict, resistance to SP has reached levels that require recon-
sideration or even change of policy.5,9A change of policy is a
difficult and time-consuming process,9and before decisions
are made, let alone implemented, resistance may have in-
creased to such a degree that a combination with another
drug may no longer be useful. This may already be true in
some areas in Kenya such as the Bungoma District where this
study was performed. Continued use of SP monotherapy in an
area of at least 40% resistance will lead to increased morbid-
ity, mortality, and costs. Combining AQ with SP in those
circumstances may not be useful; AQ with a sensitivity of
90% as monotherapy will be sufficient by itself and SP does
not increase this sensitivity. To secure a longer life for AQ, it
should be combined with an artemisinin drug, such as arte-
sunate.34In areas with less resistance, the combination of
SP with AQ may secure a longer life for both drugs. In Ken-
ya, comparative trials of SP plus AQ, AQ plus AS, and Coar-
tem? (Novartis, Basel, Switzerland) and preferably also di-
hydroartemisinin-piperaquine37are needed. Further studies
of several aspects of combination treatments such as use
during pregnancy and infancy are urgently needed, but it is
also time to act. Adequate funding is needed for these stud-
ies and for quick and large-scale implementation of their re-
Received July 2, 2003. Accepted for publication May 28, 2004.
Acknowledgments: We thank those who supported this malaria re-
search project, especially AMREF East-Africa, the Sirisia Health
Center, the Webuya Panpaper Clinic, and Bungoma Hospital in the
Bungoma District of Kenya. We are grateful to Dr. J. Reesink and
Dr. D. van de Wetering for their work in Kenya.
Financial support: This study was supported by AMREF, the Spinoza
Fund (Amsterdam University Society), and the Department of Infec-
tious Diseases, Tropical Medicine and AIDS (Academic Medical
Authors’ addresses: C. J. Vreugdenhil, F. Y. Scheper, S. R.
Hoogstraatte, and M. Smolders, Faculty of Medicine and Department
of Infectious Diseases, Tropical Medicine and AIDS, University of
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lands. S. Gikunda, Malaria Unit, African Medical and Research
Foundation, Nairobi, Kenya. F. G. Cobelens and P. A. Kager, De-
partment of Infectious Diseases, Tropical Medicine and AIDS, Aca-
demic Medical Center, F4-217, PO Box 22, 660 1000 DD Amsterdam,
The Netherlands, Telephone: 31-20-566-4380, Fax: 31-20-697-2286,
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AQ AND SP FOR THE TREATMENT OF P. FALCIPARUM MALARIA