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Increased Efficacy of Sulfadoxine-Pyrimethamine in the Treatment of Uncomplicated Falciparum Malaria among Children with Sickle Cell Trait in Western Kenya

  1. Dianne J. Terlouw1,2,3,
  2. Michael A. Aidoo1,
  3. Venkatachalam Udhayakumar1,
  4. Margarette S. Kolczak1,
  5. Aggrey J. Oloo2,a,
  6. Piet A. Kager3,
  7. Altaf A. Lal1,
  8. Bernard L. Nahlen1,2,4 and
  9. Feiko O. ter Kuile1,2,3
  1. 1Division of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia;
  2. 2Kenya Medical Research Institute, Center for Vector Biology and Control Research, Kisumu, Kenya;
  3. 3Department of Infectious Diseases, Tropical Medicine, and AIDS, Academic Medical Center, University of Amsterdam, The Netherlands;
  4. 4Roll Back Malaria, World Health Organization, Geneva, Switzerland
  1. Reprints or correspondence: Dianne J. Terlouw, Dept. of Infectious Diseases, Tropical Medicine, and AIDS, Academic Medical Center, University of Amsterdam, Meibergdreef 9, F4-217, 1105 AZ Amsterdam Zuid Oost, The Netherlands (fterkuile{at}cdc.gov)
 
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Abstract

The role of the sickle cell hemoglobin type as a determinant of treatment outcome with sulfadoxine-pyrimethamine was retrospectively studied in young children with uncomplicated falciparum malaria who lived in an area with intense perennial malaria transmission. Between 1993 and 1997, 2795 treatments involving 813 children were monitored. Sickle cell trait (HbAS) was present in 17.7% of the children. Two-and-a-half percent of the children experienced early clinical treatment failure by day 2–3, and 17.3% of the children were parasitemic on day 7. Treatments in HbAS children were less likely than those in HbAA children to result in persistence of parasitemia by day 3 (relative risk [RR], 0.66; 95% confidence interval [CI], 0.47–0.93; P=.02) or in parasitologic treatment failure on day 7 (RR, 0.51; 95% CI, 0.36–0.71; P<.0001). These results suggest that the HbAS phenotype should be included among factors that determine sulfadoxine-pyrimethamine treatment outcome

Sickle cell hemoglobin (HbS) is a mutant allele of β-globin and is one of the well-known balanced polymorphisms providing heterozygotes (HbAS) with 60%–90% protection against high-density Plasmodium falciparum parasitemia, acute uncomplicated malaria, severe malaria, and malaria mortality [1 –3]. This advantage has provided a strong selection pressure in large parts of sub-Saharan Africa with moderate-to-intense malaria transmission, resulting in high population frequencies of this mutation

Over the last decade, several countries in sub-Saharan Africa, including Kenya, have replaced or are in the process of replacing chloroquine with sulfadoxine-pyrimethamine for the first-line treatment of uncomplicated P. falciparum malaria. With a general concern that the effective life of sulfadoxine-pyrimethamine may be limited in Africa [4], close monitoring of the efficacy of this antimalarial treatment is essential for evaluating geographic variation in the development of resistance to it and assessing its durability in specific areas. In vivo antimalarial treatment failures may be caused by many factors other than the intrinsic susceptibility of P. falciparum to the antimalarial drug being tested [5]. An understanding of the different factors that influence the clinical and parasitologic response is important for the correct interpretation of estimates of drug efficacy

The presence of the sickle cell trait (HbAS) or other host-genetic factors that confer protection against malaria is seldom taken into account in the assessment of antimalarial efficacy. There are several studies suggesting that host-genetic factors play a role in determining antimalarial treatment outcome, including evidence for a reduced effect of chloroquine and artemisinin derivates against P. falciparum in α-thalassemia [6 –8]. Little is known, however, of the role of sickle cell hemoglobin. P. falciparum parasites grown in HbSS erythrocytes in vitro have been found to be less susceptible to chloroquine than those infecting HbAA erythrocytes, whereas no difference was seen between HbAS and HbAA erythrocytes [9]. Only one study has compared the treatment response with antimalarials in vivo by hemoglobin S phenotype [10]: the study, conducted in the 1980s in western Kenya, showed an enhanced response to chloroquine in HbAS children who were <10 years of age with uncomplicated malaria. To our knowledge, studies involving the potential role of the HbAS phenotype in determining treatment outcome with other antimalarials have not been published. We retrospectively studied the role of the sickle cell trait as determinant of the clinical and parasitological response to sulfadoxine-pyrimethamine in children <5 years of age with acute uncomplicated P. falciparum malaria

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Methods

Study area and populationThis study was conducted between April 1993 and March 1997 in 15 villages on the shores of Lake Victoria in western Kenya, as part of a larger ongoing community-based study of the acquisition of natural immunity to malaria in children <5 years of age (Asembo Bay Cohort project [ABCP]). The study site and design of the ABCP have been described elsewhere in detail [11, 12]. In brief, the population was ethnically homogeneous, with >95% belonging to the Luo tribe. This area has intense perennial malaria transmission, with a mean of 60–300 infected bites per year [13]. Between 60% and 90% of the children <5 years of age have detectable P. falciparum parasitemia at any time. High-grade resistance to chloroquine was widespread [14]

Each child enrolled in the ABCP was visited every 2 weeks by a village monitor. At each visit, a morbidity questionnaire was completed, which included questions on the history of antimalarial use in the previous 2 weeks, and the body temperature taken. During every other visit (i.e., every 4 weeks), the child’s weight and height were measured, and a blood sample (250–500 μL) was obtained by finger or heel prick for the determination of hemoglobin concentrations and the presence of malaria parasites. Mothers were told to bring their children to the village monitor at any time that the child was ill in between scheduled visits. In case of a documented fever (axillary temperature ⩾37.5°C), an additional malaria smear was obtained. During the study period, sulfadoxine-pyrimethamine was not widely available in the area outside of the Centers for Disease Control and Prevention/Kenya Medical Research Institute research setting. Previous analysis indicated that HbAS and HbSS occur in 17.4% and 3.3%, respectively, of infants born in the ABCP [2]. The corresponding frequencies observed in pregnant women in this study area are 23% and 0%

Design of treatment studyABCP birth-cohort children were enrolled in this treatment study if they fulfilled the following criteria: infection with microscopically detected P. falciparum (pure infections or mixed infections with either P. malariae or P. ovale); age <60 months; axillary temperature ⩾37.5°C; no signs of severe malaria (hemoglobin ⩾5.0 g/dL, parasitemia ⩽100,000/μL, and normal mental status) [15]; and no history of sulfadoxine-pyrimethamine treatment in the previous 14 days [16]. The treatment dose with sulfadoxine-pyrimethamine was one-fourth of a tablet for infants, one-half of a tablet for 1–3-year-old children, and a full tablet for 4-year-old children [17]. Each tablet contained 25 mg pyrimethamine and 500 mg sulfadoxine. The brands of sulfadoxine-pyrimethamine 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. The tablets were crushed and given with water under supervision of the village monitor. Every child was observed for 30 min to see if vomiting occurred, and, if so, the full dose was repeated

Follow-up scheduleEach child was visited at home on days 2 and 7, at which time a morbidity questionnaire was answered and the axillary temperature and a blood sample for a malaria blood smear were obtained. If the study participants could not be found on the scheduled days, the village monitor revisited the homes on days 3 or 4 and 8, 9, or 10

Laboratory methodsThick and thin blood smears were stained with Giemsa and examined for parasites. Parasite densities were counted against 300 leukocytes and expressed per cubic millimeters of blood, using an assumed leukocyte count of 8000 cells/mm3. Hemoglobin concentrations were measured using the HemoCue Hb Test System (HemoCue). Plasma and blood cell pellets were frozen at −20°C. DNA was extracted from the frozen blood cell pellets by use of the Puregene and Capture column DNA extraction kits (Gentra Systems), as directed by the manufacturer. A polymerase chain reaction method, as described by Wu et al. [18], was used to determine the presence of hemoglobin A and S

DefinitionsTreatment failures and successes were defined using a modified version of the World Health Organization (WHO) classification system [16]. Early clinical failure was defined as having either clinical deterioration requiring alternative treatment or persistence of fever with an increased P. falciparum parasitemia on day 2, compared with the pretreatment density, or persistence of any P. falciparum parasites with fever by day 3 or 4. Parasitologic treatment failure was defined as the presence of P. falciparum parasites on day 7, regardless of the presence of symptoms. Cumulative treatment failure was defined as having either an early clinical failure by day 2–4 or a parasitologic treatment failure by day 7. Halofantrine (SmithKline Beecham) at a dose of 3×8 mg/kg was used for retreatment of children experiencing clinical failures. Children were classified as stunted, underweight, or wasted if the height-for-age, weight-for-age, and weight-for-height z scores, respectively, were less than −2. Moderate anemia was defined as a hemoglobin concentration <8.0 g/dL

Data management and statistical analysisThe software packages SUDAAN (release 8; SAS callable version) and SAS (version 8.0) were used for the bivariate and multivariate analyses, respectively. Confidence intervals and P values were corrected for multiple observations per child. We estimated the association between the different phenotypes and sulfadoxine-pyrimethamine efficacy, using a binomial regression analysis in PROC GENMOD (SAS) with a log link function to obtain estimates of the adjusted risk ratios and using generalized estimating equation methods to account for multiple treatments per child [19, 20]

To verify whether associations between Hb phenotype and sulfadoxine-pyrimethamine efficacy could be attributed to confounding, factors associated with either Hb phenotype or treatment failure in bivariate analysis (P<.10) were added to the multivariate models as covariates. The following factors were considered to be potential confounders: year of study, treatment dose (in milligrams per kilogram) of sulfadoxine-pyrimethamine on the basis of body weight, history of recent chloroquine intake, and presence of pretreatment moderate anemia [21]. The following factors were considered to be potential intermediate factors: age, history of recent sulfadoxine-pyrimethamine intake, pretreatment parasite density, and nutritional z scores [21]. The differentiation between confounding and intermediate factors (which are covariates that may be affected by the exposure and represent a step in the causal path between exposure and outcome [22]) was made a priori. Intermediate factors were added as covariates because they can also be confounders [22]. None of the individual intermediate factors influenced the point estimate of the main association between phenotype and treatment failure, and all modeling could therefore be done using the GENMOD procedure [23]. Age was evaluated as an interaction term in the model (age×HbS) to assess the association between the HbAA and HbAS phenotypes and sulfadoxine-pyrimethamine efficacy in the different age groups. For all statistical tests, 2-sided P<.05 was considered to be significant

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Results

Between April 1993 and April 1997, 3166 treatments were given to 958 children who were part of the ABCP birth cohort. Overall, 3063 treatment episodes were followed-up, 83.5% could be followed-up successfully within 4 days, on day 2 (64.9%), day 3 (14.0%), or day 4 (4.6%), and 76.7% could be followed-up successfully on “day 7” (52.8% on day 7 and 24.0% on days 8–10). This resulted in an overall success rate of follow-up by day 7 of 78.8% or 2495 treatments. The Hb phenotype was available for 86.0% (824/958) of the children and 91.3% (2795/3063) of the treatments that contributed follow-up data on days 2–4 or 7 (figure 1)

Figure 1
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Figure 1

Profile of a study of hemoglobin phenotype and sulfadoxine-pyrimethamine efficacy in young children in western Kenya, 1993–1997. ABCP, Asembo Bay Cohort Project; CTF, cumulative treatment failure; ECF, early clinical failure; PTF, parasitologic treatment failure

Of the 824 children with a known HbS status, 79% had the HbAA phenotype, 17.7% had the HbAS phenotype, and 3.3% had the HbSS phenotype. There were no differences between the characteristics of the children receiving treatments that could be successfully followed until day 7 and those that were either lost to follow-up before that day or had an unknown HbS status, except that missing HbS status occurred more frequently in children born in the second half of the study (1995–1997; P<.0001)

The pretreatment characteristics of the 2795 treatments are described in table 1. Children with HbAS contributed fewer treatments (median, 2 vs. 3; P=.04), were older at the time of their first treatment, had lower-density parasitemias and less moderate anemia, and were less likely to have been treated with sulfadoxine-pyrimethamine in the previous 35 days than HbAA children. Treatments in HbAS children were associated with higher mean height-for-age Z (HAZ) scores than those in HbAA children, but this difference was not statistically significant. However, HbAS children were less likely to be stunted (HAZ score of less than −2; 27.9% vs. 36.0%; P=.03). Compared with HbAA children, HbSS children contributed fewer treatments (median, 1 vs. 3; P=.05), had significantly lower median parasite densities, were less moderately anemic, were older at their first treatment, and had lower HAZ and weight-for-age z scores than HbAA children (none of these were statistically significant)

Figure 2
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Figure 2

Cumulative treatment failure among young children in western Kenya by day 7 after treatment of uncomplicated falciparum malaria with sulfadoxine-pyrimethamine, by hemoglobin phenotype and age. Error bars represent the 95% confidence intervals (CIs) for the failure risk estimate. Ninety-five percent CIs for the relative risk (RR) are shown in parentheses

Table 1
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Table 1

Characteristics of 813 children (644 with the HbAA phenotype, 142 with the HbAS phenotype, and 27 with the HbSS phenotype) <5 years of age receiving 2795 treatments for uncomplicated falciparum malaria in western Kenya, 1993–1997

Children with HbAS were equally as likely to be parasitemic as HbAA children on day 2, but they were more likely to have cleared their parasitemia by day 3. HbAS was not associated with faster fever clearance. Overall, 2.5% (61/2413) of the treatments resulted in an early clinical failure, and 17.3% (383/2213) resulted in parasitologic treatment failure. The cumulative treatment failure risk by day 7 was 19.5% (444/2274). In both bivariate and multivariate analyses, HbAS was associated with a significantly lower parasitologic and cumulative treatment failure risk by day 7 (table 2). Although HbAS was associated with a reduced risk of cumulative treatment failure among all age groups, this association was particularly apparent in the first 6 months of life (3.1% [2/61]) versus in children 6–59 months of age (18.7% [63/337]) (figure 2). Several variables (study year, sulfadoxine-pyrimethamine dose based on body weight, moderate anemia, and recent chloroquine intake) were omitted from the final model, because they were not found to be effect modifiers or confounders or to affect the precision of the estimated effect of the HbAS phenotype on treatment outcome. Thus, to evaluate the role of the intermediate factors on the association between the hemoglobin phenotypes and treatment outcome, we compared a model with all the potential intermediate factors to the crude model. The efficacy estimates did not differ much between these 2 models for any of the outcomes. The prevalence of pure P. malariae or P. ovale infections on day 7 was similar between treatments in HbAS and HbAA children (4.9% vs. 3.4%; relative risk, 1.41; 95% confidence interval, 0.32–6.13)

Table 2
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Table 2

Results of the univariate multivariate analysis, showing Hb phenotype as a determinant of treatment failure among young children with uncomplicated falciparum malaria in western Kenya, 1993–1997

Eighty-one treatments were contributed by 27 children with HbSS. Although the risks of parasitologic and cumulative treatment failure were lower in HbSS children than in children with HbAA, none of these differences was statistically significant (table 2). The presence of pure P. malariae or P. ovale infections on day 7 was more likely in children with HbSS than HbAA (16.7% [2/12] vs. 3.4% [14/409]; P=.02)

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Discussion

We found that in this area of high malaria transmission pressure, among young children who required treatment for uncomplicated malaria, sulfadoxine-pyrimethamine was half as likely to fail for those with the sickle cell trait (HbAS) than those with normal hemoglobin (HbAA). Apart from age, this is the strongest determinant of treatment outcome in young children identified in our antimalarial treatment studies (unpublished observations). An enhanced efficacy, although less pronounced, was also seen with sickle cell anemia (HbSS), but numbers of HbSS children were small (27 children and 81 treatments), and the difference was not statistically significant

Children who carried the sickle cell trait were older at the time of their first treatment, were less likely to have received SP in the previous month, and had lower pretreatment parasite densities than children with HbAA. They were also less likely to be stunted, possibly reflecting the beneficial long-term cumulative impact on health and nutritional status because of the lower risk of clinical malaria and severe anemia [24, 25]. Age, pretreatment parasite densities (independent of age), recent sulfadoxine-pyrimethamine intake, and malnutrition are all known determinants of antimalarial efficacy [26 –30] and are also affected by the sickle cell trait. Thus, the trait could determine antimalarial treatment outcome through these intermediate factors. However, the multivariate analysis showed that only a small proportion of the lower risk of treatment failure in HbAS children could be attributed to these factors. Although the exact mechanisms of protection of the sickle cell trait against malaria morbidity are only partly understood, there are several other possible mechanisms by which HbAS might enhance the effect of sulfadoxine-pyrimethamine

There are several examples of pharmacodynamic and kinetic interactions of other antimalarials with malaria resistance genes, including with the artemisinin derivates and α-thalassemia [6, 31, 32], chloroquine and α-thalassemia [6, 8, 31], and chloroquine and HbS [33]. It is unknown, however, if such drug-specific modulation exists for sulfadoxine or pyrimethamine and the HbAS phenotype. It is possible that the uptake and or retention of either of the 2 components of sulfadoxine-pyrimethamine may be higher in HbS containing red cells infected with P. falciparum. Erythrocytes with HbS can have excess α-globin chains, which can promote lipid peroxidation by binding to red cell membranes, especially under low oxygen tension experienced by red cells infected with mature parasite stages that are cytoadhered in the microcapillary bed [34]. As a result, the membrane permeability may increase and favor the increased uptake of a drug. The increased efficacy of sulfadoxine-pyrimethamine in HbAS individuals may also be explained by physiologic and immunologic mechanisms resulting in enhanced clearance of parasites, irrespective of an impact on the uptake and/or retention of the antimalarial drug. For example, under conditions of low oxygen tension, a retardation of parasite growth and parasite invasion has been observed in vitro in nonsickled AS cells [9, 35 –37], possibly due to the loss of K+ ions caused by altered membrane permeability [34]. The natural exposure of all P. falciparum–infected erythrocytes to low oxygen tension occurs while sequestered in the deep tissues during the last half of the parasite’s asexual life-cycle, where the parasite matures to a schizont and develops merozoites. Since sulfadoxine-pyrimethamine has a narrow time-window of drug action, which targets the parasite during this schizont stage, both mechanisms would coincide and may interact to effectively kill parasites, thus preventing subsequent parasite multiplication and enhancing clearance. In addition, preferential phagocytosis of parasitized erythrocytes expressing neoantigens has been suggested as a common and powerful mechanism of protection in several red cell disorders [38, 39]. In sickle cell trait, a binding of larger amounts of antibodies to neoantigens of infected cells [40], as well as an altered immune reactivity [41], has been observed

The present treatment study is based on a retrospective analysis of data from a larger cohort study, which was not designed to look at the impact of the hemaglobin phenotype on treatment outcome with sulfadoxine-pyrimethamine. Thus, hemoglobin type was not available for 14% of the children enrolled in this treatment–follow-up study. A fifth of the treated children were lost to follow-up by day 7. The larger cohort study included routine monthly finger-prick blood samples, and, 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. Treatments in children with an unknown phenotype or without follow-up on day 2 or 7 did not differ in age, severity of illness, or other predictors of treatment outcome from those with a complete follow-up or known phenotype. Thus, this is unlikely to have been a source of substantial bias. Because low pretreatment parasite density was not an exclusion criteria in this study and because we aimed to represent early clinical failure, as opposed to early treatment failure, a modified version of the WHO criteria to define treatment outcome was used, which excluded the 75% decline in parasitemia by day 2 or 3 as a criterion for early treatment or parasitologic failure. Use of the old WHO definition for parasitologic failure by day 7, commonly used at the time this study was conducted [42], or the current WHO classification [16], which combines clinical and parasitologic criteria, did not change our results (data not shown)

Results of this study, together with those of the previous study of chloroquine efficacy in this same area [10], suggest that the sickle cell trait may enhance the effect of antimalarial drugs and that this protection extends beyond the known time interval (∼2–16 months of age) during which HbAS was previously found to contribute to reduced mortality in western Kenya [2]. Whether a similar beneficial effect of sickle cell trait on treatment outcome can be found among young children in areas of lower or more seasonal transmission pressure, as well as among semi-immune adolescents and adults, deserves further investigation

We conclude that sickle cell trait enhances the efficacy of sulfadoxine-pyrimethamine to clear P. falciparum parasites in young children with uncomplicated malaria. This is also the group usually targeted for in vivo studies of antimalarial drug efficacy in malaria-endemic areas of Africa. Thus, in areas with a high prevalence of sickle cell trait among the study population, overall estimates of drug efficacy may be somewhat higher than those seen in areas where sickle cell trait is less common. Furthermore, the improved treatment efficacy conferred by HbAS may become more apparent with the emergence of higher levels of antimalarial drug resistance, which will result in more parasites escaping the static or killing effects of the drug, requiring that host factors provide a greater contribution to the radical clearance of parasites [43]. An unequal distribution of HbAS by chance between treatment groups or over time in longitudinal monitoring studies might be an important source of bias, which is a particular problem in studies of small sample sizes. Thus, one should question whether determination of HbS should be included in the routine monitoring of antimalarial treatment efficacy. This would not be feasible in most settings in malaria-endemic countries, nor would it be indicated, as long as there is no reason to suspect that the study sample has a biased distribution of HbAS relative to the underlying population. Nevertheless, these results do suggest that the presence of hemoglobin S should be taken into account in studies that aim to determine factors that affect treatment outcome with sulfadoxine-pyrimethamine and possibly other antimalarials

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Acknowledgments

We thank the parents and guardians of the children who participated in the study and the staff who assisted with this project; the Director of the Kenya Medical Research Institute for his permission to publish this work; Peter Boland and Trent Ruebush for their contribution to the design and coordination of the fieldwork; and Larry Slutsker for reviewing this manuscript

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Footnotes

  • ↵Presented in part: 50th meeting of the American Society of Tropical Medicine and Hygiene, Atlanta, November 2001 (poster 543)

    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 in the local language of the study procedures and potential benefits and risks. This is Asembo Bay Cohort Project manuscript no. XVII

    The opinions or assertions contained in this manuscript are the private ones 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 the US Public Health Service or Department of Health and Human Services

    Financial support: The Netherlands Foundation for the Advancement of Tropical Research (WOTRO, grants W93-323 and W93-273 to D.J.T. and F.O.t.K.); US Agency for International Development (HRN 6001-A-00-4010-00, funding the Asembo Bay Cohort Project); ASM/NCID Postdoctoral Fellowship (to M.A.A.); National Center for Infectious Diseases/Centers for Disease Control and Prevention Emerging Infectious Diseases Fund (to V.U. in support of the Hb genotyping)

  • ↵Present affiliation: Department of Epidemiology and Preventive Medicine, Moi University, Eldoret, Kenya

  • Received June 11, 2002.
  • Revision received August 5, 2002.
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References

  1. 1.↵
    1. Hill AV,
    2. Allsopp CE,
    3. Kwiatkowski D,
    4. et al
    . Common West African HLA antigens are associated with protection from severe malaria. Nature 1991;352:595-600.
    CrossRefMedline
  2. 2.↵
    1. Aidoo M,
    2. Terlouw DJ,
    3. Kolczak MS,
    4. et al
    . Protective effects of the sickle cell gene against malaria morbidity and mortality. Lancet 2002;359:1311-2.
    CrossRefMedlineWeb of Science
  3. 3.↵
    1. Greenwood B,
    2. Marsh K,
    3. Snow R
    . Why do some African children develop severe malaria? Parasitol Today 1991;7:277-81.
    CrossRefMedlineWeb of Science
  4. 4.↵
    1. White NJ,
    2. Nosten F,
    3. Looareesuwan S,
    4. et al
    . Averting a malaria disaster. Lancet 1999;353:1965-7.
    CrossRefMedlineWeb of Science
  5. 5.↵
    1. White NJ
    . Why is it that antimalarial drug treatments do not always work? Ann Trop Med Parasitol 1998;92:449-58.
    CrossRefMedlineWeb of Science
  6. 6.↵
    1. Yuthavong Y,
    2. Butthep P,
    3. Bunyaratvej A,
    4. Fucharoen S
    . Decreased sensitivity of artesunate and chloroquine of Plasmodium falciparum infecting hemoglobin H and/or hemoglobin constant spring erythrocytes. J Clin Invest 1989;83:502-5.
    CrossRefMedlineWeb of Science
  7. 7.↵
    1. Senok AC,
    2. Nelson EAS,
    3. Li K,
    4. Oppenheimer SJ
    . Thalassaemia trait, red blood cell age and oxidant stress: effects on Plasmodium falciparum growth and sensitivity to artemisinin. Trans R Soc Trop Med Hyg 1997;91:585-9.
    CrossRefMedlineWeb of Science
  8. 8.↵
    1. Mockenhaupt FP,
    2. May J,
    3. Bergqvist Y,
    4. Meyer CG,
    5. Falusi AG,
    6. Bienzle U
    . Evidence for a reduced effect of chloroquine against Plasmodium falciparum in alpha‐thalassaemic children. Trop Med Int Health 2001;6:102-7.
    CrossRefMedlineWeb of Science
  9. 9.↵
    1. Nguyen‐Dinh P,
    2. Parvin RM
    . Haemoglobin S and in vitro chloroquine susceptibility of Plasmodium falciparum . Lancet 1986;2:1278.
    Medline
  10. 10.↵
    1. Brandling‐Bennett AD,
    2. Oloo AJ,
    3. Watkins WM,
    4. Boriga DA,
    5. Kariuki DM,
    6. Collins WE
    . Chloroquine treatment of falciparum malaria in an area of Kenya of intermediate chloroquine resistance. Trans R Soc Trop Med Hyg 1988;82:833-7.
    CrossRefMedlineWeb of Science
  11. 11.↵
    1. Bloland PB,
    2. Boriga DA,
    3. Ruebush TK,
    4. et al
    . Longitudinal cohort study of the epidemiology of malaria infections in an area of intense malaria transmission. II. Descriptive epidemiology of malaria infection and disease among children. Am J Trop Med Hyg 1999;60:641-8.
    Abstract
  12. 12.↵
    1. Bloland PB,
    2. Ruebush TK,
    3. McCormick JB,
    4. et al
    . Longitudinal cohort study of the epidemiology of malaria infections in an area of intense malaria transmission. I. Description of study site, general methodology, and study population. Am J Trop Med Hyg 1999;60:635-40.
    Abstract
  13. 13.↵
    1. Beier JC,
    2. Oster CN,
    3. Onyango FK,
    4. et al
    . Plasmodium falciparum incidence relative to entomologic inoculation rates at a site proposed for testing malaria vaccines in western Kenya. Am J Trop Med Hyg 1994;50:529-36.
    Abstract/FREE Full Text
  14. 14.↵
    1. Shretta R,
    2. Omumbo J,
    3. Rapuoda B,
    4. Snow RW
    . Using evidence to change antimalarial drug policy in Kenya. Trop Med Int Health 2000;5:755-64.
    CrossRefMedlineWeb of Science
  15. 15.↵
    Severe and complicated malaria. World Health Organization, Division of Control of Tropical Diseases. Trans R Soc Trop Med Hyg 1990;84 Suppl 2:1-65.
    MedlineWeb of Science
  16. 16.↵
    1. World Health Organization
    . Assessment of therapeutic efficacy of antimalarial drugs for uncomplicated malaria in areas with intense transmission [report no. WHO/MAL/96.1077]. Geneva: WHO; 1996.
  17. 17.↵
    1. Behrman RE,
    2. Kliegman RM,
    3. Jenson HB
    . Nelson textbook of pediatrics. 16th ed. Philadelphia: WB Saunders; 2000.
  18. 18.↵
    1. Wu DY,
    2. Ugozzoli L,
    3. Pal BK,
    4. Wallace RB
    . Allele‐specific enzymatic amplification of beta‐globin genomic DNA for diagnosis of sickle cell anemia. Proc Natl Acad Sci USA 1989;86:2757-60.
    Abstract/FREE Full Text
  19. 19.↵
    1. McCullagh P,
    2. Nelder JA
    . Generalized linear models. London: Chapman & Hall; 1989.
  20. 20.↵
    1. Skov T,
    2. Deddens J,
    3. Petersen MR,
    4. Endahl L
    . Prevalence proportion ratios: estimation and hypothesis testing. Int J Epidemiol 1998;27:91-5.
    Abstract/FREE Full Text
  21. 21.↵
    1. Kleinbaum DG,
    2. Kupper LL,
    3. Muller KE,
    4. Nizam A
    . Applied regression analysis and other multivariable methods. 3rd ed. Belmont, CA: Duxbury Press; 1998.
  22. 22.↵
    1. Rothman KJ,
    2. Greenland S
    1. Greenland S
    . Introduction to regression modeling. In: Rothman KJ, Greenland S, editors. Modern epidemiology. 2nd ed. Philadelphia: Lippincott‐Raven; 1998. p. 401-35.
  23. 23.↵
    1. Robins JM
    . The control of confounding by intermediate variables. Stat Med 1989;8:679-701.
    MedlineWeb of Science
  24. 24.↵
    UN Administrative Committee on Coordination: Sub‐Committee on Nutrition (ACC/SCN). Fourth report on the world nutrition situation. Geneva: ACC/SCN in collaboration with International Food Policy Research Institute; 2000.
  25. 25.↵
    1. World Health Organization
    . Physical status: the use of and interpretation of anthropometry [technical report series no. 854]. Geneva: WHO; 1995.
  26. 26.↵
    1. ter Kuile FO,
    2. Luxemburger C,
    3. Nosten F,
    4. Thwai KL,
    5. Chongsuphajaisiddhi T,
    6. White NJ
    . Predictors of mefloquine treatment failure: a prospective study of 1590 patients with uncomplicated falciparum malaria. Trans R Soc Trop Med Hyg 1995;89:660-4.
    CrossRefMedlineWeb of Science
  27. 27.↵
    1. Wolday D,
    2. Kibreab T,
    3. Bukenya D,
    4. Hodes R
    . Sensitivity of Plasmodium falciparum in vivo to chloroquine and pyrimethamine‐sulfadoxine in Rwandan patients in a refugee camp in Zaire. Trans R Soc Trop Med Hyg 1995;89:654-6.
    CrossRefMedlineWeb of Science
  28. 28.↵
    1. World Health Organization
    . Drug resistance in malaria [report no. WHO/CDS/CSR/DRS/2001.4]. Geneva: WHO; 2001.
  29. 29.↵
    1. Hess FI,
    2. Nukuro E,
    3. Judson L,
    4. Rodgers J,
    5. Nothdurft HD,
    6. Rieckmann KH
    . Anti‐malarial drug resistance, malnutrition and socio‐economic status. Trop Med Int Health 1997;2:721-8.
    CrossRefMedlineWeb of Science
  30. 30.↵
    1. Mutabingwa T,
    2. Nzila A,
    3. Mberu E,
    4. et al
    . Chlorproguanil‐dapsone for treatment of drug‐resistant falciparum malaria in Tanzania. Lancet 2001;358:1218-23.
    CrossRefMedlineWeb of Science
  31. 31.↵
    1. Vattanaviboon P,
    2. Wilairat P,
    3. Yuthavong Y
    . Binding of dihydroartemisinin to hemoglobin H: role in drug accumulation and host‐induced antimalarial ineffectiveness of alpha‐thalassemic erythrocytes. Mol Pharmacol 1998;53:492-6.
    Abstract/FREE Full Text
  32. 32.↵
    1. Charoenteeraboon J,
    2. Kamchonwongpaisan S,
    3. Wilairat P,
    4. Vattanaviboon P,
    5. Yuthavong Y
    . Inactivation of artemisinin by thalassemic erythrocytes. Biochem Pharmacol 2000;59:1337-44.
    CrossRefMedlineWeb of Science
  33. 33.↵
    1. Orjih AU
    . Increased accumulation of chloroquine and desethylchloroquine in homozygous sickle cells. Bull World Health Organ 1987;65:51-5.
    MedlineWeb of Science
  34. 34.↵
    1. Brewer GJ
    1. Friedman MJ
    . Hemoglobin and the red cell membrane: increased binding polymorphic hemoglobins and measurement of free radicals in the membrane. In: Brewer GJ, editor. The red cell. New York: Alan R. Liss; 1981. p. 519.
  35. 35.↵
    1. Pasvol G,
    2. Weatherall DJ,
    3. Wilson RJ
    . Cellular mechanism for the protective effect of haemoglobin S against P. falciparum malaria. Nature 1978;274:701-3.
    CrossRefMedline
  36. 36.↵
    1. Friedman MJ
    . Erythrocytic mechanism of sickle cell resistance to malaria. Proc Natl Acad Sci USA 1978;75:1994-7.
    Abstract/FREE Full Text
  37. 37.↵
    1. Orjih AU,
    2. Chevli R,
    3. Fitch CD
    . Toxic heme in sickle cells: an explanation for death of malaria parasites. Am J Trop Med Hyg 1985;34:223-7.
    Abstract/FREE Full Text
  38. 38.↵
    1. Luzzi GA,
    2. Merry AH,
    3. Newbold CI,
    4. Marsh K,
    5. Pasvol G,
    6. Weatherall DJ
    . Surface antigen expression on Plasmodium falciparum–infected erythrocytes is modified in alpha‐ and beta‐thalassemia. J Exp Med 1991;173:785-91.
    Abstract/FREE Full Text
  39. 39.↵
    1. Cappadoro M,
    2. Giribaldi G,
    3. O’Brien E,
    4. et al
    . Early phagocytosis of glucose‐6‐phosphate dehydrogenase (G6PD)–deficient erythrocytes parasitized by Plasmodium falciparum may explain malaria protection in G6PD deficiency. Blood 1998;92:2527-34.
    Abstract/FREE Full Text
  40. 40.↵
    1. Marsh K,
    2. Otoo L,
    3. Hayes RJ,
    4. Carson DC,
    5. Greenwood BM
    . Antibodies to blood stage antigens of Plasmodium falciparum in rural Gambians and their relation to protection against infection. Trans R Soc Trop Med Hyg 1989;83:293-303.
    CrossRefMedlineWeb of Science
  41. 41.↵
    1. Bayoumi RA
    . The sickle‐cell trait modifies the intensity and specificity of the immune response against P. falciparum malaria and leads to acquired protective immunity. Med Hypotheses 1987;22:287-98.
    CrossRefMedlineWeb of Science
  42. 42.↵
    1. World Health Organization
    . Chemotherapy of malaria and resistance to antimalarials [technical report series no. 529]. Geneva: WHO; 1973.
  43. 43.↵
    1. Cravo P,
    2. Culleton R,
    3. Hunt P,
    4. Walliker D,
    5. Mackinnon MJ
    . Antimalarial drugs clear resistant parasites from partially immune hosts. Antimicrob Agents Chemother 2001;45:2897-901.
    Abstract/FREE Full Text
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  1. J Infect Dis. (2002) 186 (11): 1661-1668. doi: 10.1086/345363
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