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Treatment history and treatment dose are important determinants of sulfadoxinepyrimethamine efficacy in children with uncomplicated malaria in western Kenya
Terlouw, D.J.; Courval, J.M.; Kolczak, M.S.; Rosenberg, O.S.; Oloo, A.J.; Kager, P.A.; Lal,
A.A.; Nahlen, B.L.; ter Kuile, F.O.
Published in:
The Journal of Infectious Diseases
DOI:
10.1086/367705
Link to publication
Citation for published version (APA):
Terlouw, D. J., Courval, J. M., Kolczak, M. S., Rosenberg, O. S., Oloo, A. J., Kager, P. A., ... ter Kuile, F. O.
(2003). Treatment history and treatment dose are important determinants of sulfadoxine-pyrimethamine efficacy
in children with uncomplicated malaria in western Kenya. The Journal of Infectious Diseases, 187, 467-476. DOI:
10.1086/367705
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Download date: 14 Jun 2017
MAJOR ARTICLE
Treatment History and Treatment Dose Are
Important Determinants of SulfadoxinePyrimethamine Efficacy in Children
with Uncomplicated Malaria in Western Kenya
Dianne J. Terlouw,1,2,3 Jeanne M. Courval,1 Margarette S. Kolczak,1 Oren S. Rosenberg,1,2,a Aggrey J. Oloo,2,a
Piet A. Kager,3 Altaf A. Lal,1 Bernard L. Nahlen,1,2,4 and Feiko O. ter Kuile1,2,3
1
Division of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia; 2Kenya
Medical Research Institute, Center for Vector Biology and Control Research, Kisumu, Kenya; 3Department of Infectious Diseases, Tropical
Medicine, and AIDS, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 4Roll Back Malaria, World Health
Organization, Geneva, Switzerland
This study retrospectively studied amendable determinants of sulfadoxine-pyrimethamine (SP) efficacy involving 2869 treatments among 1072 Kenyan children !5 years old who had uncomplicated malaria. The dose
was based on age: one-quarter tablet was given to infants !1 year old, one-half tablet was given to 1–3-yearold children, and a full tablet was given to 4-year-old children. Only 23.5% received the internationally
recommended target dose of 25/1.25 mg of SP per kg of body weight. SP intake in the previous 15–35 days
(adjusted relative risk, 1.67; 95% confidence interval, 1.35–2.07) and low SP dose (!27.5/1.375 mg/kg) (adjusted
relative risk, 1.58; 95% confidence interval, 1.17–2.13) explained 38% of parasitological treatment failures by
day 7. Patients with recent SP intake are likely to have recrudescent infections and may need close follow-up
if treated with SP or alternative treatment. Applying our weight-for-age data to 31 existing age-based SP dose
recommendations predicted that 22 of them would result in underdosing of 125% of children !5 years. Many
age-based dose recommendations need urgent revision, because SP is increasingly used as first-line treatment
in sub-Saharan Africa.
Over the last decade, 11 countries in sub-Saharan Africa
have replaced, or are in the process of replacing, chloroquine (CQ) with sulfadoxine-pyrimethamine (SP) or
a combination of CQ plus SP for first-line treatment
of uncomplicated Plasmodium falciparum malaria. The
long half-lives of sulfadoxine and pyrimethamine (180
and 95 h, respectively) [1] favor the selection of resistant parasites [2, 3], and there is a general concern that
Received 10 July 2002; revised 1 October 2002; electronically published 24
January 2003.
Financial support: Netherlands Foundation for the Advancement of Tropical
Research (grants W93-323 and W93-273 to D.J.T. and F.O.t.K.); US Agency for
International Development (grant HRN 6001-A-00-4010-00 to the Asembo Bay
Cohort Project).
a
Present affiliations: Department of Cell Biology, Yale University School of
Medicine, New Haven, Connecticut (O.S.R); Department of Epidemiology and
Preventive Medicine, Moi University, Eldoret, Kenya (A.J.O.).
Reprints or correspondence: Dr. Feiko O. ter Kuile, Malaria Epidemiology Branch,
Centers for Disease Control and Prevention, Mailstop F-22, 4770 Buford Hwy, NE,
Atlanta, GA 30341-3724 ([email protected]).
The Journal of Infectious Diseases 2003; 187:467–76
2003 by the Infectious Diseases Society of America. All rights reserved.
0022-1899/2003/18703-0015$15.00
Presented in part: 46th meeting of the American Society for Tropical Medicine
and Hygiene (ASTMH), Lake Buena Vista, Florida, December 1997 (abstract no.
13); 50th ASTMH meeting, Atlanta, November 2001 (abstract no. 542).
This study was approved by the institutional review boards of the Kenya Medical
Research Institute and the Centers for Disease Control and Prevention. Informed
consent was obtained from all caregivers after explanation of the study procedures
in the local language.
This is Asembo Bay Cohort Project manuscript number XVIII.
The opinions or assertions contained in this manuscript are those of the authors
and are not to be construed as official or reflecting the views of the US Public
Health Service or Department of Health and Human Services. Use of trade names
is for identification only and does not imply endorsement by US Public Health
Service or Department of Health and Human Services.
Amendable Determinants of SP Efficacy • JID 2003:187 (1 February) • 467
the effective life of SP monotherapy may be limited in Africa
[2, 3]. In Thailand, SP replaced CQ in the early 1970s, but,
within 5 years, radical cure rates by day 28 had dropped from
83% in 1975 to 22% in 1979 [4]. Increasing treatment failure
rates with SP have also been observed recently in northeastern
Tanzania and Kenya [5–7]. In most of the remaining part of
sub-Saharan Africa, however, it remains very effective [8, 9],
which suggests that there is considerable geographical variation
in the development and distribution of SP resistance. Close
monitoring of SP efficacy will be necessary to assess its durability in specific areas.
In vivo antimalarial treatment failures may be caused by
insufficient drug concentrations, host factors, parasite factors
(including drug resistance), or a combination of them [10].
Although all these factors can cause treatment failure in the
individual, they may also contribute to the development and
intensification of parasite drug resistance in the population by
increasing the likelihood of exposure of parasites to suboptimal
drug levels [10, 11]. Knowledge of the determinants of SP
treatment outcome will help to identify individual patients who
are at risk of treatment failure and will assist in the adequate
interpretation of treatment outcome in comparative antimalarial treatment studies or longitudinal surveillance of SP efficacy. They also help to identify modifiable factors that may
contribute to the development of resistance. We studied these
putative, modifiable determinants of SP treatment outcome
among children !5 years old with symptomatic uncomplicated
falciparum malaria in western Kenya.
PATIENTS, MATERIALS, AND METHODS
Study area and population. This study was conducted between April 1993 and April 1997 in 15 villages in Rarieda Division on the shores of Lake Victoria in western Kenya, as part
of a larger ongoing community based study of the acquisition
of natural immunity in children !5 years old (Asembo Bay
Cohort Project [ABCP]). The study site and methodology have
been described in detail elsewhere [12, 13]. In brief, the population was ethnically homogeneous, with 195% belonging to
the Luo tribe. Of the children enrolled in the ABCP, 17.4% had
sickle cell trait [14]. This area has intense perennial malaria
transmission, with a mean range of 60–300 infected bites/person/year [15]. Of the children !5 years old, 60%–90% have
detectable P. falciparum parasitemia at any time [16]. More
than 95% of these infections are due to P. falciparum, and
almost all of the remainder are due to P. malariae. Infections
with P. ovale are rare [13]. High-grade resistance to CQ is
widespread [17].
Mothers were enrolled during pregnancy, together with their
newborns and other children !5 years old. Each child enrolled
in the ABCP was visited every 2 weeks by a village monitor,
468 • JID 2003:187 (1 February) • Terlouw et al.
who was a resident in the same village. At each visit, a morbidity
questionnaire was completed, which included questions on the
history of antimalarial use in the previous 2 weeks, and the
axillary temperature was taken. At every other visit (approximately monthly), the child’s weight and height were measured,
and a blood sample (250–500 mL) was taken by finger or heel
prick for the determination of hemoglobin concentrations and
the presence of malaria parasites. Mothers were asked to bring
their children to the village monitor in between scheduled visits
whenever they thought their child was ill. In case of a documented fever (temperature, ⭓37.5C), an additional malaria
smear was taken. During the study period, SP was not widely
available in the area outside of the Centers for Disease Control
and Prevention (CDC)/Kenya Medical Research Institute research setting, but it was introduced as part of the new national
malaria treatment policy in late 1998 through early 1999.
Study design and procedures. The current treatment study
was nested within the larger ABCP, as described elsewhere [18].
Children were enrolled in the treatment study if they fulfilled
the following criteria: age 0–59 months, axillary temperature
⭓37.5C, no signs of severe malaria (hemoglobin ⭓5g/dL, parasitemia ⭐100,000/mL, and normal mental status) [19], no history of SP treatment in the previous 14 days [20], and P. falciparum infection (pure or mixed species).
The dose of SP in this study was, as in many parts of Africa,
based on age, as opposed to body weight, and was designed to
obtain an average of 25/1.25 mg/kg SP, the internationally recommended target dose. Infants were given one-quarter tablets,
1–3-year-old children were given one-half tablets, and 4-yearold children were given full tablets [21]. Each tablet contained
25 mg of pyrimethamine and 500 mg of sulfadoxine. The
brands of SP used during the 4-year study period were Fansidar
(Hoffman–La Roche), Falcidin (Cosmos), and Orodar (Elys
Chemical Industries). The quality of the local brands was confirmed by high-performance liquid chromatography in the
CDC laboratories in Atlanta. The tablets were crushed and given
with water under supervision of the study staff. Every child
was observed for 30 min to see if vomiting occurred, and, if
so, the full dose was repeated. Hemoglobin concentrations were
measured using the Haemocue method (Haemocue). Each
child was visited at home on days 2 and 7, at which time a
morbidity questionnaire was completed, and the axillary temperature and a malaria blood smear were taken. If the study
participants could not be found on the scheduled days, the
village monitor revisited the homes on day 3 or 4 and day 8,
9, or 10.
Definitions. Treatment failures and successes were defined
using a modified version of the World Health Organization
(WHO) classification system [22]. Early clinical failure (ECF)
was defined as either clinical deterioration requiring alternative
treatment or persistence of fever with pure or mixed falciparum
parasitemia on day 2 that was greater than the pretreatment
density or persistence of any P. falciparum parasites with fever
by day 3 or 4 [22]. Parasitological treatment failure (PTF) was
defined as the presence of P. falciparum parasites on days 7–10,
regardless of the presence of symptoms. The presence of other
plasmodium species in the absence of P. falciparum was not
considered to be a treatment failure in this analysis. Cumulative
treatment failure (CTF) by day 7 was defined as having either
an ECF by days 2–4 or a PTF by days 7–10. Clinical treatment
failures were retreated according to WHO guidelines [22] with
halofantrine (Halfan 3 ⫻ 8 mg/kg; SmithKlineBeecham), which
is effective in the retreatment of mulidrug resistant P. falciparum
malaria [23]. The use of halofantrine as retreatment antimalarial was discontinued in 1996 after the discovery of its potential adverse cardiac effects [24]; it was replaced by amodiaquine [20].
Determinants studied. We retrospectively studied the following putative determinants of treatment failure: age, sex, year
of treatment, season, history of recent SP or CQ treatment,
pretreatment parasite density, axillary temperature, infection
with mixed or pure plasmodium species, gametocytemia, hemoglobin level, SP dose in milligrams per kilogram of body
weight, nutritional status (weight-for-age, weight-for-height,
and height-for-age z scores ⭐2), number of days of symptoms
prior to treatment, and sickle cell hemoglobin (HbS) phenotype
[18, 25–30]. Three of these determinants were considered to
be amendable: SP dose, history of recent CQ treatment, and
history of recent SP treatment.
Estimates of over- and underdosing. The potential risk of
over- and underdosing were calculated for different age-based
dose recommendations for SP. This was done using a weightfor-age data set containing weight relative to age from a random
sample of 3575 children enrolled in cross-sectional surveys as
part of a larger study of the impact of insecticide-treated bed
nets on childhood morbidity and mortality conducted between
1996 and 1999 [31]. This analysis was done weighted for “malaria risk,” with young children contributing relatively more to
the analysis than older children. This weight factor was based
on the age distribution of 120,000 children treated for malaria
in peripheral health clinics in the same study area over a 4year period between 1995 and 1999. To compare the different
dose regimens an index score for over- and underdosing was
calculated as (1 ⫻ proportion underdosed) ⫹ (5 ⫻ proportion
overdosed), where underdosing was defined as !25/1.25 mg/
kg SP, and overdosing as 170/3.5 mg/kg SP. The definition of
overdosing was based on the increased risk of severe bone
marrow depression resulting in potentially fatal megaloblastic
anemia described for pyrimethamine doses above this threshold
[32]. Overdosing was given, arbitrarily, 5 times more weight
than underdosing, because the risk of potentially fatal adverse
events due to overdosing was considered to be more serious
than treatment failure due to underdosing.
Data management and statistical analysis. Data forms
were checked, coded, and entered using Clarion software (Topspeed/Soft Velocity). Data were cleaned using range and internal consistency checks. Confidence intervals (CIs) and P values were corrected for multiple observations per child in both
univariate and multivariate analysis. Variables associated with
treatment outcome in the univariate analysis (P ! .10 ) were
included in the full multivariate model. All models were created using Proc Genmod, a procedure within the SAS software package (version 8.0; SAS Institute), by use of a log-link
function and a binomial distribution [33]. Age and study year
were always forced into the model. All other factors included
in the full model were considered to be candidates for removal.
The population attributable fraction (PAF) was calculated as
follows: [prevalence ⫻ (RR ⫺ 1)]/1 ⫹ [prevalence ⫻ (RR ⫺ 1)],
where “RR” denotes “relative risk.” The overall PAF for a combination of determinants (which is not additive) was calculated as follows: 1 ⫺ [(1 ⫺ PAF1) ⫻ (1 ⫺ PAF2 ) ⫻ … ⫻ (1 ⫺ PAFn]
[34]. For all statistical tests, a 2-sided P ! .05 was considered
to be significant.
RESULTS
Patient characteristics. Between April 1993 and April 1997,
3620 treatments were given to 1195 children. The median number of treatments per child was 2 (interquartile range [IQR],
1–5 treatments). Of all treatments, 42.6% (1543) were given to
infants, and the proportion of treatments given to older children declined with age (1 year, 29.0%; 2 years, 14.8%; 3 years,
9.0%; and 4 years, 4.7%). Overall, 82.9% (3001/3620) of treatments could be followed up successfully on either day 2
(64.2%), day 3 (13.7%), or day 4 (5.0%), and 78.0% (2823/
3620) were followed up on “day 7” (54.3% on day 7 and 23.7%
on days 8–10). This resulted in an overall success rate of followup by day 7 of 79.3% (2869 treatments). The baseline characteristics of these 2869 treatments are summarized in table 1.
There were no differences between the characteristics of the
treatments followed-up successfully and those lost to followup by day 7, except for the year of study, with lower followup rates at the very beginning and at the very end of the study
(data not shown). Overall, 2.2% (66/3001) of the treatments
resulted in an ECF, and 16.6% (465/2803) resulted in a PTF.
The CTF risk by day 7 was 18.5% (531/2869).
Determinants of treatment failure. The only independent
determinant of ECF was age. ECF was most prevalent during
the first 2 years of life (age !24 months vs. ⭓24 months: RR,
3.4; 95% CI, 1.4–8.2) (figure 1). Age was also a determinant
of PTF, although, unlike ECF, the risk of PTF increased with
age until age 3 years. By contrast, 4-year-old children were at
Amendable Determinants of SP Efficacy • JID 2003:187 (1 February) • 469
Table 1.
Univariate analysis of factors associated with cumulative treatment failure by day 7.
Variable
n
Male
2869
Age, median months (IQR)
2869
Year of study
2869
All patients
1388 (48.4)
14.4 (8.0–26.9)
Patients with
treatment success
(n p 2338)
Patients with
treatment failure
(n p 531)
1119 (47.9)
269 (50.7)
14.1 (7.9–27.3)
15.4 (8.4–26.0)
April 1993– March 1995
1553 (54.1)
1286 (55.0)
267 (50.3)
April 1995– March 1997
1316 (45.9)
1052 (45.0)
264 (49.7)
Axillary temperature, mean C (SE)
2599
Parasite density, geometric mean (95% CI)
2869
38.3 (0.02)
6108 (5692–6554)
38.3 (0.02)
6163 (5709–6653)
38.3 (0.04)
5871 (5079–6786)
1–4999 parasites/mL
975 (34.0)
820 (35.1)
155 (29.2)
5000–14,999 parasites/mL
826 (28.8)
636 (27.2)
190 (35.8)
⭓15,000 parasites/mL
1068 (37.2)
882 (37.7)
186 (35.0)
2869
192 (6.7)
159 (6.8)
33 (6.2)
Gametocytes
2850
170 (6.0)
140 (6.0)
30 (5.7)
Hemoglobin, mean g/dL (SE)
2263
Mixed vs. pure species
Hemoglobin !8.0 g/dL
9.3 (0.06)
9.4 (0.06)
9.1 (0.12)
642 (28.4)
505 (27.5)
137 (32.4)
AA
1867 (82.1)
1472 (80.4)
395 (89.0)
AS
344 (15.1)
305 (16.7)
39 (8.8)
SS
63 (2.8)
53 (2.9)
10 (2.3)
HbS phenotype
P
.29
.52
.06
.45
.54
.0008
.61
.76
.06
.05
2274
!.0001
Wasted, WHZ ! ⫺2
2702
65 (2.4)
54 (2.5)
11 (2.2)
.69
Stunted, HAZ ! ⫺2
2775
980 (35.3)
801 (35.4)
179 (34.9)
.83
Underweight, WAZ ! ⫺2
2763
394 (14.3)
328 (14.6)
66 (12.7)
.23
2 (2–4)
.32
Severity symptoms
Duration of fever, median days (IQR)
2869
Temperature 139C plus vomiting
1659
SP dose, mean mg/kg (SE)
Pyrimethamine !1.375 mg/kg
2726
2 (2–4)
2 (2–4)
179 (10.8)
1.06 (0.007)
152 (11.3)
1.06 (0.007)
27 (8.5)
1.03 (0.01)
.13
.01
2726
2321 (85.1)
1866 (84.1)
455 (89.6)
.0015
SP Rx in previous 15–35 days
2869
340 (11.9)
240 (10.3)
100 (18.8)
.0001
CQ Rx in previous 2 weeks
2869
521 (18.2)
427 (18.3)
94 (17.7)
.76
NOTE. Data are no. (%) of patients, except where noted. There were 2869 treatments among 1072 children !5 years old. CI, confidence
interval; CQ, chloroquine; HAZ, height-for-age x score; HbS, sickle cell hemoglobin; IQR, interquartile range; Rx, treatment; SP, sulfadoxinepyrimethamine; WAZ, weight-for-age x score; WHZ, weight-for-height x score.
a markedly lower risk of PTF (7.1%) (figure 1). Apart from
age, the following factors were associated with treatment failure
(PTF and CTF) in univariate analysis (P ! .10 ) and were considered for evaluation in a multivariate model: study year, HbS
phenotype, pretreatment parasite density, and pretreatment hemoglobin level (all nonamendable factors), and history of recent SP intake and SP dose in mg/kg based on body weight
(both amendable factors) (table 1). At the time of the study,
SP was not widely available in this area outside of the ABCP
infrastructure. During the whole study period, caretakers reported 35 SP treatments that could not be accounted for in
our study records and that, presumably, were obtained outside
the study setting. The history of recent SP intake could, therefore, be reliably assessed using the SP treatment records from
the study.
470 • JID 2003:187 (1 February) • Terlouw et al.
In subsequent multivariate analysis (after adjusting for the
nonamendable risk factors that were retained in the model [i.e.,
age, study year, parasite density, and HbS phenotype]), recent
SP intake and SP dose were found to be strong predictors of
PTF and CTF by day 7 (table 2). This effect of recent SP intake
was evident for a period up to 35 days (figure 2). Among the
3620 treatments, 428 (11.8%) were associated with a history
of SP intake in the previous 15–35 days (10.4% among children
!1 year old and 12.9% among older children). The median
dose obtained with this regimen was 20.2/1.01 mg/kg SP (IQR,
0.83–1.25 mg/kg SP), and more than three-fourths of the doses
received (76.2%) were !25/1.25 mg/kg, the internationally recommended target dose. Comparison of sensitivity, specificity,
and Youden’s index scores showed that a dose of 27.5/1.375
mg/kg SP was the most discriminative threshold concentration
(figure 4). This indicated that important variation exists in
current treatment recommendations for SP in young children.
Almost all recommendations that specifically mention a target
dose in mg/kg use 25/1.25 mg/kg SP, and a minority recommend 20/1.00 mg/kg [65–68]. One recent guideline from
UNICEF recommends doses lower than this [69]. Overall, 31
age-based dose recommendation for children !5 years old could
be identified, representing 11 different variations. Overdosing
was rare for all regimens. However, underdosing was predicted
to occur in 125% of the children at 22 of the 31 dose recommendations. The dose used in the current study was recommended by most of the American textbooks [36–49], either
as monotherapy or in combination or subsequent to oral quinine. The dose recommended by the Oxford Textbook of Medicine [35] resulted in the lowest overall dose, with 79.2% of
children predicted to receive !1.25 mg/kg. The different dose
recommendations by the WHO resulted in the highest proportion of adequate dosing [59, 60, 62, 64]. The groups at
particular risk for underdosing in the most commonly used
age based regimens were the 6–12-month-old infants (if onefourth tablet instead of one-half tablet is used) and the 3 and
4 year-old children (if one-half tablet is used instead of threefourths or a full tablet) (figure 5).
Figure 1. Crude failure risk, by age. CTF, cumulative treatment failure
by day 7; ECF, early clinical failure; PTF, parasitological treatment failure.
below which an increased risk of treatment failure was observed
(figure 3 and table 2). Overall, 85.2% of the treatments received
were at a dose below 27.5/1.375 mg/kg. The rates of PTF and
CTF in the group who had both risk factors were 28.0% (82/
293) and 29.9% (90/301), respectively, compared with 10.3%
(38/369) and 12.4% (47/378), respectively, in the group with
no recent SP intake and who received ⭓27.5/1.375 mg/kg.
PAF. The PAFs for PTF and CTF were calculated for these
2 preventable determinants of treatment failure. For CTF, this
was 24.0% for SP doses !27.5/1.375 mg/kg and 7.1% for recent
SP intake in the previous 15–35 days (table 2). The overall
preventable PAF, which is not additive, was 29.6%, which suggests that, with this given level of drug resistance and age distribution, more than one-fourth of all instances of CTF can
potentially be prevented when sufficient dosing and alternative
retreatment guidelines are used. The corresponding overall PAF
for PTF was 38.0%.
Comparison of recent and current SP treatment guidelines. We were surprised that, with our age-based dose regimen, such a large proportion of children in our study had
received less than the target dose of 25/1.25 mg/kg SP recommended by the WHO when calculated against the body
weight of the child. We, therefore, reviewed recent and current
international dose recommendations for SP for children !5
years old from WHO, UNICEF, and key pediatric, infectious
diseases, and tropical medicine text books (English language)
Table 2.
DISCUSSION
We retrospectively identified 2 preventable, independent determinants of treatment outcome with SP in children !5 years
old with uncomplicated falciparum malaria. A low SP dose
based on body weight (milligrams/kilograms) and a history of
SP intake in the previous 5 weeks explained approximately onethird of all treatment failures and may contribute to the development or intensification of SP resistance.
In contrast to several previous studies of predictors of treatment efficacy [25–29], we observed a trend towards increasing
failure risk by day 7 with increasing age in the age group !3
years old (figure 1). This result was unexpected, because natural
immunity is acquired rapidly in this area of intense malaria
transmission and, as a result, older children typically show better treatment responses [25–29]. The lower failure risk in the
!6-month-old versus 6–12-month-old infants can be explained
Modifiable determinants of treatment failure: multivariate analysis.
CTF
PTF
Variable
RR (95% CI)
P
SP intake in previous 15–35 days
1.67 (1.35–2.07)
!.0001
SP dose !27.5/1.375 mg/kg
1.58 (1.17–2.13)
.003
PAF, %
RR (95% CI)
P
7.3
1.65 (1.36–2.01)
!.0001
33.1
1.37 (1.05–1.81)
.02
PAF, %
7.1
24.0
NOTE. Data were adjusted for sickle cell hemoglobin phenotype, parasite density, age, and year of study. CI, confidence
interval; CTF, cumulative treatment failure (i.e., early clinical failure on day 2–4 or any parasitemia on day 7–10); PAF, population
attributable fraction; PTF, parasitological treatment failure (i.e, any parasitemia on day 7–10); RR, relative risk.
Amendable Determinants of SP Efficacy • JID 2003:187 (1 February) • 471
Figure 2. Relationship between the history of recent sulfadoxinepyrimethamine (SP) intake (X-axis) and the probability of cumulative treatment failure following (re)treatment with SP (Y-axis). The second Y-axis
represents the relative risk (RR) of cumulative treatment failure, with the
group who had no history of SP treatment in the previous 56 days as
the reference group. The error bars represent the 95% confidence intervals
for the RRs, corrected for multiple observations per child. The dotted
horizontal line indicates a RR of 1. Each point represents the failure risk
at the mean value for each of the categories (15–21, 22–28, 29–35,
36–42, 43–49, 50–56, and 156 days since last SP treatment). Retreatment
with SP within 14 days was an exclusion criterion.
by the presence of protective factors in the very young infants,
such as fetal hemoglobin and maternal antibodies against malaria. A likely explanation for the increasing proportion of failures with age is the impact of underdosing. The dose of SP in
this study was, as in many parts of Africa, determined by age,
as opposed to weight. As children grow older, and become
heavier, they receive relatively less drug per kilogram of body
weight within a given dose/age category. This was particularly
evident in the 2- and 3-year-old children who had received
one-half tablet; 93.7% of them had received less than the recommended target dose of 25/1.25 mg/kg SP, as opposed to
1.4% of the 4-year-old-children, who all had received a full
tablet. The CTF rate was only 7.1% in the 4-year-old children,
compared with 20.5% in the 2- and 3-year-old children. Although better acquired immunity in the 4-year-olds is likely to
have contributed to this difference, the association between
treatment failure and low dose in milligrams per kilogram of
body weight was found to be independent of age (i.e., treatment
was more likely to fail in heavier children regardless of age;
table 2). One other study has also documented an association
in vivo between antimalarial treatment dose and treatment failure in adults [70].
The review of the literature indicated that weight-based dose
recommendations usually indicate a “target” dose of 1.25 mg/
kg pyrimethamine and 25 mg/kg sulfadoxine. However, there
appears considerable variation in age-based dose recommendations (figure 4). Although the original dose recommendation
by WHO includes a one-half tablet for infants and a full tablet
for 1–5-year-old children [64], aiming at 25/1.25mg/kg as a
472 • JID 2003:187 (1 February) • Terlouw et al.
minimum dose, most other recommendations result in lower
doses. Age-based dose regimens such as those previously recommended by the Kenyan Ministry of Health [71] or by Hoffmann–La Roche, the manufacturer of Fansidar [53, 72], as well
as those used in our study [36–] are widely deployed in subSaharan Africa and result in a large proportion of children !5
years old receiving !25/1.25 mg/kg SP (figure 4). Suboptimal
dosing is believed to be a major determinant of the rate at
which antimalarial drug resistance develops [11, 70, 73, 74].
Selection and persistence of resistant strains will increase the
risk of transmission and, hence, the biomass of resistant genotypes in the population [10]. Patients whose infections respond slowly to treatment or recrudesce subsequently are more
likely to carry gametocytes than those whose respond rapidly
or are cured [75–77]. SP is known to stimulate infective gametocytemia more than any other antimalarial [78, 79].
To address these concerns, WHO recently updated their dose
recommendations for SP using a large weight-for-age reference
population of 1100,000 preschool children from countries where
malaria is endemic [62]. This indicated that adequate age-based
dosing can be achieved with minimal risk to overdosing [62].
Toxicity due to pyrimethamine results in reversible (by folate
supplementation) dose-dependent hematological effects associated with bone marrow depression, including life threatening
megaloblastic anemia, leukopenia, and thrombocytopenia. The
Figure 3. Relationship between treatment dose (in milligrams) of pyrimethamine (lower X-axis) and sulfadoxine (upper X-axis) received per
kilogram of body weight and the probability of a treatment failure by day
7 (cumulative treatment failure). Error bars represent the 95% confidence
intervals for values on the left Y-axis, corrected for multiple observations
per child. Each point represents the failure risk at the mean value for
each of the 6 dose categories (0–0.84, 0.85–1.04, 1.05–1.24, 1.25–1.44,
1.45–1.64, and ⭓1.65 mg/kg). The right Y-axis represents the relative
risk of treatment failure, with the highest dose group as the reference.
The 2 vertical dotted lines represent the internationally recommended
target dose of 25/1.25 mg/kg sulfadoxine-pyrimethamine and 27.5/1.375
mg/kg sulfadoxine pyrimethamine; the most discriminative dose which
differentiates between treatment failure and success.
Figure 4. Recent and current age-based treatment guidelines for sulfadoxine-pyrimethamine (SP) in children !5 years old. aRecommended as
monotherapy [20, 3551, 53–60, 62–65] or combined with oral quinine or chloroquine [36–50, 52, 61, ]. bOne tablet of SP contains 500 mg of sulfadoxine
and 25 mg of pyrimethamine. cNr, not recommended. dProportion of children 2–59 months old predicted to receive !25/1.25 mg/kg (underdosing), 25/
1.25–70/3.5 mg/kg (adequate dosing), and 170/3.5 mg/kg (overdosing) of SP. eAdequate dose index score p (1 ⫻ proportion !1.25 mg/kg pyrimethamine
) ⫹ (5 ⫻ proportion 13.5 mg/kg pyrimethamine). The lower the score, the better the result. fPopulation attributable fraction (PAF) is based on the
proportion of children predicted to receive !27.5/1.375 mg/kg sulfadoxine/pyrimethamine and a relative risk of treatment failure by day 7 of 1.37
(table 2). gNa, not assessed because of lack of dose recommendation for children 2–5 months old.
threshold dose associated with severe bone marrow depression
is not well known, particularly in children, but doses !3.5mg/
kg are usually considered to be acceptable [31]. Although severe,
potentially fatal, skin reactions to sulfonamide have been reported, this has been reported mainly associated with prophylactic use [80]. When used as a single treatment dose, the risk
appears to be low (estimated 1:50,000 to 1:200,000 for single
dose treatment with SP at doses between 25/1.25 and 42/2.0 mg/
kg) [81–83].
We also found that children who received SP within the
previous 15–35 days had a 1.7 times higher failure risk by day
7 than those who had no history of recent SP intake, probably
reflecting an increased likelihood that these are retreatments of
recrudescent infections with a selected parasite population of
resistant genotypes (figure 2). In the absence of molecular genotyping, we cannot distinguish between treatment failure (recrudescence) and new infections (reinfection). However, these
results are consistent with a study in Tanzanian children !5
years old where parasite DNA was studied for point mutations
in the genes encoding dihydrofolate reductase and dihydropteroate synthetase [6, 7].
This result suggests that, in settings where treatment is based
on microscopy results, patients should be provided with alternative antimalarial therapy if they have a history of SP use in
the previous month, instead of the currently recommended 14day period [20]. This is particularly relevant in young children
Figure 5. Proportion of children !5 years old predicted to be underdosed or overdosed by sulfadoxine-pyrimethamine (SP) treatment dose and age
group. One tablet of SP contains 500 mg of sulfadoxine and 25 mg of pyrimethamine. The nos. before and after the commas represent the proportion
of children predicted to receive !25/1.25mg/kg (underdosing) and 170/3.5 mg/kg (overdosing) of SP, respectively.
Amendable Determinants of SP Efficacy • JID 2003:187 (1 February) • 473
with high-density parasitemias and insufficient host-immunity
to clear surviving resistant parasites [10]. However, in rural
settings, treatment is often based on fever instead of microscopy
and, thus, is less specific for malaria, and alternative treatment
may not be widely available. In those settings, a febrile patient
with a history of SP in the previous month requires malaria
diagnostics where available and may benefit from closer followup of this SP “retreatment.”
These results also have implications for surveillance of SP
efficacy. When excluding children who had a history of SP in
the previous 35 days and those who had received a treatment
dose of !27.5/1.37 mg/kg SP, the CTF rate was 12.4%, versus
29.9% among those with both risk factors and 18.5% in the
overall study population. When not taking these factors into
account, the “true” SP resistance by day 7 will thus be overestimated. Furthermore, with increasing resistance, a higher
percentage of the study population is likely to have been exposed to the study drug within the previous month. Thus, the
history of SP in the previous month should either be added as
an exclusion criterion or should be adjusted for in subsequent
analyses. These results also suggest that the failure rates assessed
on day 7 or 14 underestimate resistance in the population. With
slowly eliminated drugs such as SP, most recrudescences in areas
with predominantly low grade resistance occur 114 days after
treatment, because this is the time required to reach patent
parasitemia from low parasite numbers with multiplication
rates being suppressed by host defenses and residual inhibitory
concentrations of the drug [10, 84].
We used a modified version of the WHO criteria to define
early treatment outcome in this study. We excluded the 75%
decline in parasitemia by day 2 or 3 as criterion for early treatment or parasitological failure, because low pretreatment parasite density was not an exclusion criterion in this study, and
we aimed to represent ECF, as apposed to early treatment failure. Use of the old WHO definition for parasitological failure
by day 7 [31], commonly used at the time this study was
conducted, or the current WHO classification [22], which combines clinical and parasitological criteria, did not change the
conclusion (data not shown).
The relatively low success rate of follow-up in this study
deserves further mention. This treatment study was nested in
a larger ongoing cohort study of children !5 years old, which
included routine monthly finger pricking. Although most caregivers consented to treatment follow-up, a relatively high proportion subsequently refused to have their child pricked for
the additional day 2 and day 7 treatment follow-up visits. Although treatments without follow-up on day 2 or 7 did not
differ in age, severity of illness, or any other characteristics at
the time of treatment from those with a complete follow-up,
refusal is more likely to occur for children who are clinically
474 • JID 2003:187 (1 February) • Terlouw et al.
improved and this may have resulted in an overestimation of
the clinical failure risk in particular.
There is an urgent need to reevaluate the dosing guidelines
for SP, because most existing dose recommendations result in
considerable underdosing. This is particularly timely, because
it is expected that several more African countries will replace
CQ with SP, or combination therapy including SP, within the
near future. We recommend that, when feasible, antimalarial
dosing should be based on body weight. However, this is not
an option in most settings in sub-Saharan Africa. If antimalarial
treatment guidelines for SP are based on age, they should aim
to obtain a minimum, rather than average, target dose of 25/
1.25 mg/kg SP. For most sub-Saharan African populations of
preschool children, the new WHO age-based dose recommendation [62] will result in adequate dosing for 195% of them,
with minimal risk of overdosing.
Acknowledgments
We thank the parents and guardians of the children who
participated in the study; the many people who assisted with
this project; the Director of the Kenya Medical Research Institute (Nairobi, Kenya) for his permission to publish this work;
Peter Bloland and Trent Ruebush (Centers for Disease Control
and Prevention [CDC], Atlanta) for their contribution to the
design and coordination of the fieldwork; and Larry Slutsker
and Rick Steketee (CDC) for critical review of the manuscript.
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