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Background: Despite scale-up of seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine and amodiaquine (SP-AQ) in children 3-59 months of age in Burkina Faso, malaria incidence remains high, raising concerns regarding SMC effectiveness and selection of drug resistance. Using a case-control design, we determined associations between SMC drug levels, drug resistance markers, and presentation with malaria., Methods: We enrolled 310 children presenting at health facilities in Bobo-Dioulasso. Cases were SMC-eligible children 6-59 months of age diagnosed with malaria. Two controls were enrolled per case: SMC-eligible children without malaria; and older (5-10 years old), SMC-ineligible children with malaria. We measured SP-AQ drug levels among SMC-eligible children and SP-AQ resistance markers among parasitemic children. Conditional logistic regression was used to compute odds ratios (ORs) comparing drug levels between cases and controls., Results: Compared to SMC-eligible controls, children with malaria were less likely to have any detectable SP or AQ (OR, 0.33 [95% confidence interval, .16-.67]; P = .002) and have lower drug levels (P < .05). Prevalences of mutations mediating high-level SP resistance were rare (0%-1%) and similar between cases and SMC-ineligible controls (P > .05)., Conclusions: Incident malaria among SMC-eligible children was likely due to suboptimal levels of SP-AQ, resulting from missed cycles rather than increased antimalarial resistance to SP-AQ., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Intermittent preventive treatment of malaria during pregnancy (IPTp) with dihydroartemisinin-piperaquine (DP) provides greater protection from placental malaria than sulfadoxine-pyrimethamine (SP). Some studies suggest placental malaria alters risk of malaria infection in infants, but few have quantified the effect of IPTp on infant susceptibility to malaria., Methods: Infants born to women enrolled in a randomized clinical trial comparing IPTp-SP and IPTp-DP in Malawi were followed from birth to 24 months to assess effect of IPTp and placental malaria on time to first malaria episode and Plasmodium falciparum incidence., Results: In total, 192 infants born to mothers randomized to IPTp-SP and 195 randomized to IPTp-DP were enrolled. Infants in IPTp exposure groups did not differ significantly regarding incidence of clinical malaria (incidence rate ratio [IRR], 1.03; 95% confidence interval [CI], .58-1.86) or incidence of infection (IRR, 1.18; 95% CI, .92-1.55). Placental malaria exposure was not associated with incidence of clinical malaria (IRR, 1.03; 95% CI, .66-1.59) or infection (IRR, 1.15; 95% CI, .88-1.50). Infant sex, season of birth, and maternal gravidity did not confound results., Conclusions: We did not find evidence that IPTp regimen or placental malaria exposure influenced risk of malaria during infancy in this population. Clinical Trials Registration. NCT03009526., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Mutations in the Plasmodium falciparum genes Pfdhfr and Pfdhps, particularly the sextuple mutant haplotype threatens the antimalarial effectiveness of sulfadoxine-pyrimethamine (SP) as intermittent preventive treatment during pregnancy (IPTp). To explore the impact of sextuple mutant haplotype infections on outcome measures after provision of IPTp with SP, we monitored birth outcomes in women followed up from before conception or from the first trimester until delivery. Women infected with sextuple haplotypes, in the early second trimester specifically, delivered newborns with a lower birth weight compared with women who did not have malaria during pregnancy (difference, -267 g; 95% confidence interval, -454 to -59; P = .01) and women infected with less SP-resistant haplotypes (-461 g; -877 to -44; P = .03). Thus, sextuple haplotype infections seem to affect the effectiveness of SP for IPTp and directly affect birth outcome by lowering birth weight. Close monitoring and targeted malaria control during early pregnancy is therefore crucial to improving birth outcomes., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Clinical trials of interventions for preventing malaria in pregnancy often use measures of malaria at delivery as their primary outcome. Although the objective of these interventions is to improve birth outcomes, data on associations between different measures of malaria at delivery and adverse birth outcomes are limited., Methods: Data came from 637 Ugandan women enrolled in a randomized controlled trial of intermittent preventive treatment of malaria in pregnancy. Malaria at delivery was detected using peripheral and placental blood microscopy, placental blood loop-mediated isothermal amplification (LAMP), and placental histopathology. Multivariate analyses were used to estimate associations between measures of malaria at delivery and risks of low birth weight (LBW), small for gestational age (SGA), and preterm birth (PTB)., Results: Detection of malaria parasites by microscopy or LAMP was not associated with adverse birth outcomes. Presence of malaria pigment detected by histopathology in ≥30% of high-powered fields was strongly associated with LBW (adjusted risk ratio [aRR] = 3.42, P = .02) and SGA (aRR = 4.24, P < .001) but not PTB (aRR = 0.88, P = .87)., Conclusions: A semiquantitative classification system based on histopathologically detected malaria pigment provided the best surrogate measure of adverse birth outcomes in a high-transmission setting and should be considered for use in malaria in pregnancy intervention studies., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Sulfadoxine-pyrimethamine (SP) is used as intermittent preventive therapy in pregnancy (IPTp) for malaria in sub-Saharan Africa. The resistance marker dhps A581G has been associated with reduced IPTp-SP efficacy and enhanced morbidity in SP recipients., Methods: We measured SP-resistance allele frequencies in Malawian women participating in a trial comparing IPTp with SP against intermittent screening by rapid diagnostic tests (ISTp). We genotyped polymerase chain reaction-detected parasites using deep sequencing of SP-resistance alleles., Results: Among 125 placental infections, A581G-bearing parasites were associated with reduced birth weight (mean difference [MD], 252 g; 95% confidence interval [CI], 46-457; P = .017). Relative to ISTp, IPTp-SP was associated with higher birth weights in women with wild-type parasites (MD, 116 g; 95% CI, -40 to 272; P = .142) and lower birth weights in women with A581G-bearing parasites (MD, 192 g; 95% CI, -264 to 648; P = .385) (Pinteraction = .033). Similar associations were noted on gestational age (Pinteraction = .075). Amongst only IPTp-SP recipients, relative to women who last received SP > 4 weeks before delivery, recent SP receipt was associated with lower birth weight in women with wild-type parasites (MD, 118 g; 95% CI, -376 to 139; P = .361) and higher birth weight in women with A581G-bearing parasites (MD, 783 g; 95% CI, -20 to 1586; P = .054) (Pinteraction = .005)., Conclusions: The effectiveness in birth weight of IPTp-SP is compromised by A581G-bearing parasites, but there was no evidence that the adverse effects of these parasites are exacerbated by antenatal SP., Isrctn Registry: www.isrctn.com/ISRCTN69800930., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Innovative approaches are needed to limit antimalarial resistance evolution. Understanding the role of intermittent preventive treatment in pregnancy (IPTp) on the selection for resistance and the impact such selection has on pregnancy outcomes can guide future interventions., Methods: Plasmodium falciparum isolates (n = 914) from 2 randomized clinical trials were screened for pfmdr1 copy number variation and pfcrt, pfmdr1, pfdhfr, and pfdhps resistance markers. The trials were conducted between 2010 and 2013 in Benin, Gabon, Kenya, and Mozambique to establish the efficacy of IPTp-mefloquine (MQ) compared with IPTp-sulphadoxine-pyrimethamine (SP) in human immunodeficiency virus (HIV)-uninfected and to IPTp-placebo in HIV-infected women., Results: In HIV-uninfected women, the prevalence of pfcrt mutants, pfdhfr/pfdhps quintuple mutants, and pfmdr1 copy number was similar between women receiving IPT-SP and IPTp-MQ. However, prevalence of pfmdr1 polymorphism 86Y was lower in the IPTp-MQ group than in the IPTp-SP group, and within the IPTp-MQ group it was lower at delivery compared with recruitment. No effect of IPTp-MQ on resistance markers was observed among HIV-infected women. The carriage of resistance markers was not associated with pregnancy outcomes., Conclusions: Selection of wild-type pfmdr1 polymorphism N86 by IPTp-MQ highlights the strong selective pressure IPTp can exert and the opportunity for using negative cross-resistance in drug choice for clinical treatment and IPTp., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Seasonal malaria chemoprevention (SMC) is a novel strategy to reduce malaria infections in children. Infection with Plasmodium falciparum results in immune dysfunction characterized by elevated expression of markers associated with exhaustion, such as PD1 and LAG3, and regulatory CD4+FOXP3+ T cells., Methods: In the current study, the impact of seasonal malaria chemoprevention on malaria-induced immune dysfunction, as measured by markers associated with exhaustion and regulatory T cells, was explored by flow cytometry., Results: Children that received seasonal malaria chemoprevention had fewer malaria episodes and showed significantly lower fold changes in CD4+PD1+ and CD4+PD1+LAG3+ compared to those that did not receive SMC. Seasonal malaria chemoprevention had no observable effect on fold changes in CD8 T cells expressing PD1 or CD160. However, children receiving SMC showed greater increases in CD4+FOXP3+ T regulatory cells compared to children not receiving SMC., Conclusions: These results provide important insights into the dynamics of malaria-induced changes in the CD4 T-cell compartment of the immune system and suggest that the reduction of infections due to seasonal malaria chemoprevention may also prevent immune dysfunction., Clinical Trials Registration: NCT02504918., (Published by Oxford University Press for the Infectious Diseases Society of America 2019.)

Background: Although consensus exists that malaria in pregnancy (MiP) increases the risk of malaria in infancy, and eventually nonmalarial fevers (NMFs), there is a lack of conclusive evidence of benefits of MiP preventive strategies in infants., Methods: In Burkina Faso, a birth cohort study was nested to a clinical trial assessing the effectiveness of a community-based scheduled screening and treatment of malaria in combination with intermittent preventive treatment with sulfadoxine-pyrimethamine (CSST/IPTp-SP) to prevent placental malaria. Clinical episodes and asymptomatic infections were monitored over 1 year of follow-up to compare the effect of CSST/IPTp-SP and standard IPTp-SP on malaria and NMFs., Results: Infants born during low-transmission season from mothers receiving CSST/IPTp-SP had a 26% decreased risk of experiencing a first clinical episode (hazard ratio, 0.74 [95% confidence interval, .55-0.99]; P = .047). CSST/IPTp-SP interacted with birth season and gravidity to reduce the incidence of NMFs. No significant effects of CSST/IPTp-SP on the incidence of clinical episodes, parasite density, and Plasmodium falciparum infections were observed., Conclusions: Our findings indicate that CSST/IPTp-SP strategy may provide additional protection against both malaria and NMFs in infants during the first year of life, and suggest that malaria control interventions during pregnancy could have long-term benefits in infants.

Background: Recent evidence demonstrated improved birth outcomes among human immunodeficiency virus (HIV)-uninfected pregnant women protected by indoor residual spraying of insecticide (IRS). Evidence regarding its impact on HIV-infected pregnant women is lacking., Methods: Data were pooled from 2 studies conducted before and after an IRS campaign in Tororo, Uganda, among HIV-infected pregnant women who received bed nets, daily trimethoprim-sulfamethoxazole, and combination antiretroviral therapy at enrollment. Exposure was the proportion of pregnancy protected by IRS. Adverse birth outcomes included preterm birth, low birth weight, and fetal or neonatal death. Multivariate Poisson regression with robust standard errors was used to estimate risk ratios., Results: Of 565 women in our analysis, 380 (67%), 88 (16%), and 97 (17%) women were protected by IRS for 0%, >0% to 90%, and >90% of their pregnancy, respectively. Any IRS protection significantly reduced malaria incidence during pregnancy and placental malaria risk. Compared with no IRS protection, >90% IRS protection reduced preterm birth risk (risk ratio, 0.35; 95% confidence interval, .15-.84), with nonsignificant decreases in the risk of low birth weight (0.68; .29-1.57) and fetal or neonatal death (0.24; .04-1.52)., Discussion: Our exploratory analyses support the hypothesis that IRS may significantly reduce malaria and preterm birth risk among pregnant women with HIV receiving bed nets, daily trimethoprim-sulfamethoxazole, and combination antiretroviral therapy., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: In a recent trial of intermittent preventive treatment in pregnancy (IPTp) in Uganda, dihydroartemisinin-piperaquine (DP) was superior to sulfadoxine-pyrimethamine (SP) in preventing maternal and placental malaria., Methods: We compared genotypes using sequencing, fluorescent microsphere, and quantitative polymerase chain reaction assays at loci associated with drug resistance in Plasmodium falciparum isolated from subjects receiving DP or SP., Results: Considering aminoquinoline resistance, DP was associated with increased prevalences of mutations at pfmdr1 N86Y, pfmdr1 Y184F, and pfcrt K76T compared to SP (64.6% vs 27.4%, P < .001; 93.9% vs 59.2%, P < .001; and 87.7% vs 75.4%, P = .03, respectively). Increasing plasma piperaquine concentration at the time of parasitemia was associated with increasing pfmdr1 86Y prevalence; no infections with the N86 genotype occurred with piperaquine >2.75 ng/mL. pfkelch13 propeller domain polymorphisms previously associated with artemisinin resistance were not identified. Recently identified markers of piperaquine resistance were uncommon and not associated with DP. Considering antifolate resistance, SP was associated with increased prevalence of a 5-mutation haplotype (pfdhfr 51I, 59R, and 108N; pfdhps 437G and 581G) compared to DP (90.8% vs 60.0%, P = .001)., Conclusions: IPTp selected for genotypes associated with decreased sensitivity to treatment regimens, but genotypes associated with clinically relevant DP resistance in Asia have not emerged in Uganda., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Pregnancy-associated Plasmodium falciparum infection impacts the health of mothers and newborns, but little is known about the effects of these infections on infant susceptibility to malaria. We followed 473 mother-infant pairs during pregnancy and through 2 years of age. We observed that children born to mothers with placental malaria, but not those born to mothers with peripheral infection without evidence of placental sequestration, had increased risk of malaria during the first year of life compared with children born to mothers with no malaria during pregnancy. Malaria infections with placental sequestration have long-lasting impact on infant susceptibility to malaria infection., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: In 2007, Malawi replaced sulfadoxine-pyrimethamine (SP) with an artemisinin-based combination therapy as the first-line treatment for uncomplicated Plasmodium falciparum malaria in response to failing SP efficacy. Here we estimate the effect of reduced SP pressure on the prevalence of SP-resistant parasites and the characteristics of the associated selective sweeps flanking the resistance loci., Methods: Samples obtained from individuals with clinical malaria during a period of high SP use (1999-2001), a transitional period (2007-2008), and a period of low SP use (2012) were genotyped for resistance markers at pfdhfr-ts codons 51, 59, and 108 and pfdhps codons 437, 540, and 581. Expected heterozygosity was estimated to evaluate the genetic diversity flanking pfdhfr-ts and pfdhps., Results: An increase in the prevalence of the resistance haplotypes DHFR 51I/59R/108N and DHPS 437G/540E occurred under sustained drug pressure, with no change in haplotype prevalence 5 years after reduction in SP pressure. The DHPS 437G/540E/581G haplotype was observed in 2007 and increased in prevalence during a period of reduced SP pressure. Changes to the sweep characteristics flanking pfdhfr-ts and pfdhps were minimal., Conclusions: In contrast to the rapid and complete return of chloroquine-susceptible falciparum malaria after chloroquine was withdrawn from Malawi, a reemergence of SP efficacy is unlikely in the near future., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: The A581 G: mutation in the gene encoding Plasmodium falciparum dihydropteroate synthase (dhps), in combination with the quintuple mutant involving mutations in both dhps and the gene encoding dihydrofolate reductase (dhfr), the so-called sextuple mutant, has been associated with increased placental inflammation and decreased infant birth weight among women receiving intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP) during pregnancy., Methods: Between 2009 and 2011, delivering women without human immunodeficiency virus infection were enrolled in an observational study of IPTp-SP effectiveness in Malawi. Parasites were detected by polymerase chain reaction (PCR); positive samples were sequenced to genotype the dhfr and dhps loci. The presence of K540 E: in dhps was used as a marker for the quintuple mutant., Results: Samples from 1809 women were analyzed by PCR; 220 (12%) were positive for P. falciparum. A total of 202 specimens were genotyped at codon 581 of dhps; 17 (8.4%) harbored the sextuple mutant. The sextuple mutant was associated with higher risks of patent infection in peripheral blood (adjusted prevalence ratio [aPR], 2.76; 95% confidence interval [CI], 1.82-4.18) and placental blood (aPR 3.28; 95% CI, 1.88-5.78) and higher parasite densities. Recent SP use was not associated with increased parasite densities or placental pathology overall and among women with parasites carrying dhps A581 G: ., Conclusions: IPTp-SP failed to inhibit parasite growth but did not exacerbate pathology among women infected with sextuple-mutant parasites. New interventions to prevent malaria during pregnancy are needed urgently., (Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: Malaria during pregnancy is associated with low birth weight and increased perinatal mortality, especially among primigravidae. Despite increasing prevalence of malarial parasite resistance to sulfadoxine-pyrimethamine (SP), SP continues to be recommended for intermittent preventive treatment in pregnancy (IPTp)., Methods: Women without human immunodeficiency virus infection were enrolled upon delivery. Data on the number of SP doses received during pregnancy were recorded. The primary outcome was placental infection demonstrated by histologic analysis. Secondary outcomes included malaria parasitemia (in peripheral, placental, cord blood specimens) at delivery and composite birth outcome (small for gestational age, preterm delivery, or low birth weight). RESULTS.: Of 703 women enrolled, 22% received <2 SP doses. Receipt of ≥ 2 SP doses had no impact on histologically confirmed placental infection. IPTp-SP was associated with a dose-dependent protective effect on composite birth outcome in primigravidae, with an adjusted prevalence ratio of 0.50 (95% confidence interval [CI], .30-.82), 0.30 (95% CI, .19-.48), and 0.18 (95% CI, .05-.61) for 1, 2, and ≥ 3 doses, respectively, compared with 0 doses., Conclusions: IPTp-SP did not reduce the frequency of placental infection but was associated with improved birth outcomes. Few women received no SP, so the true effect of IPTp-SP may be underestimated. Malawian pregnant women should continue to receive IPTp-SP, but alternative strategies and antimalarials for preventing malaria during pregnancy should be investigated.

Background: Pregnancy-associated malaria (PAM) produces poor birth outcomes, but its prevalence is commonly estimated in convenience samples., Methods: We assessed the prevalence of malaria using real-time polymerase chain reaction (PCR) and estimated the consequences of infection on birth outcomes, using specimens from a nationally representative sample of 4570 women of childbearing age (WOCBA) responding to the 2007 Demographic and Health Survey in Democratic Republic of the Congo (DRC)., Results: Overall, 31.2% (95% confidence interval [CI], 29.2-33.1) of WOCBA were parasitemic, which was significantly more common in pregnant (37.2% [31.0-43.5]) than nonpregnant women (30.4% [CI, 28.4-32.5], prevalence ratio [PR] 1.22 [1.02-1.47]). Plasmodium falciparum was highest among pregnant women (36.6% vs 28.8%, PR 1.27 [1.05-1.53]). By contrast, P malariae was less common in pregnant (0.6%) compared with nonpregnant women (2.7%, PR 0.23 [0.09-0.56]). Extrapolation of the prevalence estimate to the population at risk of malaria in DRC suggests 1.015 million births are affected by P falciparum infection annually, and that adherence to preventive measures could prevent up to 549 000 episodes of pregnancy-associated malaria and 47 000 low-birth-weight births., Conclusions: Pregnancy-associated malaria and its consequences are highly prevalent in the DRC. Increasing the uptake of malaria preventive measures represents a significant opportunity to improve birth outcomes and neonatal health.

Background: There is some consensus that malaria in pregnancy may negatively affect infant's mortality and malaria morbidity, but there is less evidence concerning the factors involved., Methods: A total of 1030 Mozambican pregnant women were enrolled in a randomized, placebo-controlled trial of intermittent preventive treatment with sulfadoxine-pyrimethamine, and their infants were followed up throughout infancy. Overall mortality and malaria morbidity rates were recorded. The association of maternal and fetal risk factors with infant mortality and malaria morbidity was assessed., Results: There were 58 infant deaths among 997 live-born infants. The risk of dying during infancy was increased among infants born to women with acute placental infection (odds ratio [OR], 5.08 [95% confidence interval (CI), 1.77-14.53)], parasitemia in cord blood (OR, 19.31 [95% CI, 4.44-84.02]), low birth weight (OR, 2.82 [95% CI, 1.27-6.28]) or prematurity (OR, 3.19 [95% CI, 1.14-8.95]). Infants born to women who had clinical malaria during pregnancy (OR, 1.96 [95% CI, 1.13-3.41]) or acute placental infection (OR, 4.63 [95% CI, 2.10-10.24]) had an increased risk of clinical malaria during infancy., Conclusions: Malaria infection at the end of pregnancy and maternal clinical malaria negatively impact survival and malaria morbidity in infancy. Effective clinical management and prevention of malaria in pregnancy may improve infant's health and survival.

Background: Effectiveness of cotrimoxazole (CTX) compared with sulfadoxine-pyrimethamine (SP) intermittent-preventive-therapy (IPTp) for malaria in HIV-infected pregnant women is unknown. We examined effectiveness of CTX with or without SP-IPTp versus SP-IPTp at reducing malaria parasitemia and anemia., Methods: From 2005 to 2009, we conducted a cross-sectional study of HIV-infected pregnant women at Thyolo Hospital, Malawi. Blood was tested for malaria parasitemia and anemia (hemoglobin<11 g/dl). Data were collected on use of anti-malaria interventions and other risk factors. CTX prophylaxis policy for HIV-infected pregnant women was introduced in 2007, but implementation problems resulted in some women receiving both CTX and SP-IPTp., Findings: We enrolled 1,142 women, of whom 1,121 had data on CTX and/or SP-IPTp intake. Of these, 49.7%, 29.8%, and 15.4% reported taking SP-IPTp only, CTX only and SP-IPTp plus CTX, respectively. Compared with women taking SP-IPTp, those taking SP-IPTp plus CTX and CTX were less likely to have malaria parasitemia (OR, [95%CI]: 0.09, [0.01-0.66] and 0.43, [0.19-0.97], respectively) or anemia (PR, [95% CI]: 0.67, [0.54-0.83] and 0.72, [0.61-0.83], respectively)., Conclusion: In HIV-infected pregnant women, daily CTX was associated with reduced malaria parasitemia and anemia compared with SP-IPTp. CTX plus SP-IPTp was associated with further reduction in malaria parasitemia but toxicity was not fully assessed.

Recently, the World Health Organization emphasized the potential benefit of intermittent preventive treatment in infants (IPTi) to control malaria and officially recommended implementation of IPTi with sulfadoxine-pyrimethamine (SP) in areas with moderate and high transmission, where SP resistance is not high. As reported rebound effects make further observation mandatory, we performed a survey of participants of a former IPTi trial. Malariometric parameters were similar in the SP and the placebo group. In contrast, anti-Plasmodium falciparum lysate immunoglobulin G antibody levels, a proxy measure for preceding malaria episodes, remained lower in the SP arm. The most likely explanation is a lower overall exposure to parasitic antigens after IPTi.

Background: Plasmodium falciparum parasites that cause malaria in pregnancy express unique variant surface antigens (VSAs). Levels of immunoglobulin G (IgG) antibody to pregnancy-associated VSAs measured at delivery are gravidity dependent, and they have been associated with protection from disease. It is not known how these IgG responses develop in pregnant women receiving intermittent preventive treatment during pregnancy (IPTp) or whether IgG levels in early pregnancy predict pregnancy outcomes., Methods: We performed longitudinal measurements of IgG antibody to VSAs by flow cytometric analysis of serum samples obtained from 549 Malawian women receiving IPTp. We examined fluctuations in IgG levels over time and associated the IgG levels noted at study enrollment with clinical outcomes., Results: Levels of IgG antibody to pregnancy-associated VSAs were gravidity dependent. Overall, levels decreased while women were receiving IPTp, but the levels of the individuals were highly dynamic. Primigravidae developed low levels of pregnancy-specific IgG, which were often boosted during second pregnancies. The prevalence of parasites was low (8.4% at enrollment and 2.4% in late pregnancy). Antibody levels at enrollment did not predict birth weight, duration of gestation at delivery, or the maternal hemoglobin level in late pregnancy., Conclusion: Levels of IgG antibody to pregnancy-specific VSAs decrease during receipt of IPTp. Antibody levels in early pregnancy did not predict clinical outcome. IPTp and decreasing malaria prevalence pose challenges for the evaluation of novel interventions for malaria during pregnancy.

In the context of a trial studying intermittent preventive sulfadoxine-pyrimethamine treatment of malaria in infants in Lambaréné, Gabon, children aged 18-30 months were followed up after having received their last dose at an age of 15 months. In the intention-to-treat population, the protective efficacy against all malaria episodes was -18.0 (95% confidence interval, -97.4 to 29.5; P = .529). The protective efficacy against first or only anemia episode was -45.3 (95% confidence interval, -234.5 to 36.3; P=.375). The protective efficacies were negative and were not statistically significant. These results do not appear to support the concept of a rebound effect after intermittent preventive sulfadoxine-pyrimethamine treatment of malaria in infants. Clinical trials registration. NCT00167843.

Background: In the context of the increasing resistance to sulfadoxine-pyrimethamine (SP), we evaluated the efficacy of mefloquine (MQ) for intermittent preventive treatment during pregnancy (IPTp)., Methods: A multicenter, open-label equivalence trial was conducted in Benin from July 2005 through April 2008. Women of all gravidities were randomized to receive SP (1500 mg of sulfadoxine and 75 mg of pyrimethamine) or 15 mg/kg MQ in a single intake twice during pregnancy. The primary end point was the proportion of low-birth-weight (LBW) infants (body weight, <2500 g; equivalence margin, 5%)., Results: A total of 1601 women were randomized to receive MQ (n=802)or SP (n=799).In the modified intention-to-treat analysis, which assessed only live singleton births, 59 (8%) of 735 women who were given MQ and 72 (9.8%) of 730 women who were given SP gave birth to LBW infants (difference between low birth weights in treatment groups, -1.8%; 95% confidence interval [CI], -4.8% to 1.1%]), establishing equivalence between the drugs. The per-protocol analysis showed consistent results. MQ was more efficacious than SP in preventing placental malaria (prevalence, 1.7% vs 4.4% of women; P = .005),clinical malaria (incidence rate, 26 cases/10,000 person-months vs. 68 cases/10,000 person-months; P = .007) and maternal anemia at delivery (as defined by a hemoglobin level <10 g/dL) (prevalence, 16% vs 20%; marginally significant at P = .09). Adverse events (mainly vomiting, dizziness, tiredness, and nausea) were more commonly associated with the use of MQ (prevalence, 78% vs 32%; P < 10(-3)) One woman in the MQ group had severe neuropsychiatric symptoms., Conclusions: MQ proved to be highly efficacious--both clinically and parasitologically--for use as IPTp. However, its low tolerability might impair its effectiveness and requires further investigations.

Background: We compared sulfadoxine-pyrimethamine (SP) with unsupervised artemether-lumefantrine (AL) and unsupervised amodiaquine-artesunate (ASAQ) fixed-dose formulation for the treatment of uncomplicated malaria in children in Benin., Methods: This open-label, noninferiority comparative trial included children aged 6-60 months. The follow-up period was 6 weeks, and the primary objective was a comparison of polymerase chain reaction (PCR)-adjusted effectiveness rates at day 28., Results: The study included 240 children (48 received SP, and 96 each received AL and ASAQ). The intention-to-treat analysis showed effectiveness rates on day 28 of 20.8%, 78.1%, and 70.5% for SP, AL, and ASAQ, respectively. After adjustment for PCR results, these rates were 27.1%, 83.3%, and 87.4%, respectively. The per-protocol analysis (217 patients) showed effectiveness rates on day 28 of 21.7%, 88.0%, and 76.1% for SP, AL, and ASAQ, respectively. After adjustment for PCR results, these rates were 28.3%, 94.0%, and 93.2%, respectively. SP was less effective than the other drugs in the PCR-adjusted analysis, whereas AL and ASAQ were equally effective. The rate of new infection was higher among children treated with ASAQ than among those treated with AL., Conclusions: This was the first trial, to our knowledge, to compare unsupervised AL with unsupervised ASAQ fixed-dose formulation; both treatments provided high PCR-adjusted day 28 effectiveness rates. Efficacy rates for SP were surprisingly low. Clinical trials registration. NCT00460369.

Background: Artemether-lumefantrine (AL) is a major and highly effective artemisinin-based combination therapy that is becoming increasingly important as a new first-line therapy against Plasmodium falciparum malaria. However, recrudescences occurring after AL treatment have been reported. Identification of drug-specific parasite determinants that contribute to treatment failures will provide important tools for the detection and surveillance of AL resistance., Methods: The findings from a 42-day follow-up efficacy trial in Tanzania that compared AL with sulfadoxine-pyrimethamine (SP) were analyzed to identify candidate markers for lumefantrine tolerance/resistance in the chloroquine resistance transporter gene (pfcrt) and multidrug resistance gene 1 (pfmdr1). The findings were corroborated in vitro with genetically modified isogenic P. falciparum parasite lines., Results: Treatment with AL selected for the chloroquine-susceptible pfcrt K76 allele (P < .0001) and, to a lesser extent, the pfmdr1 N86 (P = .048) allele among recurrent infections. These genotypes were not selected during SP treatment. No pfmdr1 gene amplifications were observed. Isogenic pfcrt-modified parasite lines demonstrated a 2-fold increase in susceptibility to lumefantrine, which was directly attributable to the K76T mutation., Conclusions: Our findings suggest that the pfcrt K76T mutation is a drug-specific contributor to enhanced P. falciparum susceptibility to lumefantrine in vivo and in vitro, and they highlight the benefit of using AL in areas affected by chloroquine-resistant P. falciparum malaria.

Background: Improved control efforts are reducing the burden of malaria in Africa but may result in decreased antimalarial immunity., Methods: A cohort of 129 children aged 1-10 years in Kampala, Uganda, were treated with amodiaquine plus sulfadoxine-pyrimethamine for 396 episodes of uncomplicated malaria over a 29-month period as part of a longitudinal clinical trial., Results: The risk of treatment failure increased over the course of the study from 5% to 21% (hazard ratio [HR], 2.4 per year [95% confidence interval {CI}, 1.3-4.3]). Parasite genetic polymorphisms were associated with an increased risk of failure, but their prevalence did not change over time. Three markers of antimalarial immunity were associated with a decreased risk of treatment failure: increased age (HR, 0.5 per 5-year increase [95% CI, 0.2-1.2]), living in an area of higher malaria incidence (HR, 0.26 [95% CI, 0.11-0.64]), and recent asymptomatic parasitemia (HR, 0.06 [95% CI, 0.01-0.36]). In multivariate analysis, adjustment for recent asymptomatic parasitemia, but not parasite polymorphisms, removed the association between calendar time and the risk of treatment failure (HR, 1.5 per year [95% CI, 0.7-3.4]), suggesting that worsening treatment efficacy was best explained by decreasing host immunity., Conclusion: Declining immunity in our study population appeared to be the primary factor underlying decreased efficacy of amodiaquine plus sulfadoxine-pyrimethamine. With improved malaria-control efforts, decreasing immunity may unmask resistance to partially efficacious drugs.

Use of intermittent preventive treatment with sulfadoxine-pyrimethamine (SP) during pregnancy (IPTp-SP) has become policy in much of sub-Saharan Africa but crucially depends on the efficacy of SP. We assessed the frequency of the dhfr triple mutation among Plasmodium falciparum isolates obtained from pregnant Ghanaian women in 1998, 2000, and 2006. The prevalence of the triple mutation, which confers resistance to SP, doubled from 36% to 73% during the study period (P<.001). In 2006, the prevalence was virtually identical among women of early gestation and delivering women with or without a history of IPTp-SP use, indicating that such treatment did not select for mutant parasites. Nevertheless, IPTp-SP may be outdated by drug resistance before it is fully implemented.

Unlabelled: Sulfadoxine-pyrimethamine (SP) inhibits folate metabolism by the malaria parasite. We investigated the association between folate levels and SP failure in pregnant women. Data from a trial to assess the effect that folate supplementation has on SP failure in 467 pregnant women were analyzed. Plasma folate levels were determined at enrollment and at day 7. High baseline folate levels, high parasite densities, and age <20 years were risk factors for SP failure. High-dose (5 mg daily) folate supplementation or high folate levels at day 7 were independent risk factors. Therefore, pregnant women receiving SP should receive low-/moderate-dose folate supplementation., Trial Registration: http://www.clinicaltrials.gov identifier: NCT00130065.

Background: The use of sulfadoxine-pyrimethamine (SP) for intermittent preventive treatment in pregnancy (IPTp) is threatened by the spread of resistance to SP. Therefore, we studied the efficacy, safety, and tolerance of amodiaquine (AQ) or the combination of AQ and SP (SPAQ) as possible alternative treatments., Methods: The study was performed in Ghana from June 2004 through February 2007. Women were individually randomized to receive IPTp with SP (n=1328), AQ (n= 986), or SPAQ (n=1328). Incidences of anemia, peripheral anemia, and placental parasitemia at delivery were assessed for paucigravidae, as were the birth weights of their infants. Delivery outcomes and the incidence of adverse events were investigated for all women., Results: The prevalences of anemia (as defined by a hemoglobin concentration of <11.0 g/dL) at delivery were comparable between the SP and AQ groups and between the SP and SPAQ groups. Similarly, there was no significant difference between the SP and AQ groups or between the SP and SPAQ groups with regard to the incidences of low birth weight (LBW). Women who received AQ or SPAQ were more likely to report adverse events than were those who received SP., Conclusion: The effects of IPTp with AQ or SPAQ on maternal anemia and LBW were comparable to the effects of IPTp with SP; however, IPTp regimens that contain AQ are unlikely to be useful as an alternative to IPTp with SP in Ghana, because of a high frequency of associated adverse events., Trial Registration: Clinicaltrials.gov identifier: NCT00146783 .

Background: Although malaria treatment aims primarily to eliminate the asexual blood stages that cause illness, reducing the carriage of gametocytes is critical for limiting malaria transmission and the spread of resistance., Methods: Clinical and parasitological responses to the fixed-dose combination of sulfadoxine and pyrimethamine in patients with uncomplicated falciparum malaria were assessed biannually since implementation of this treatment policy in 1998 in Mpumalanga Province, South Africa., Results: Despite sustained cure rates of > 90% (P = .14), the duration of gametocyte carriage increased from 3 to 22 weeks (per 1000 person-weeks) between 1998 and 2002 (P < .001). The dhfr and dhps mutations associated with sulfadoxine-pyrimethamine resistance were the most important drivers of the increased gametocytemia, although these mutations were not associated with increased pretreatment asexual parasite density or slower asexual parasite clearance times. The geometric mean gametocyte duration and area under the gametocyte density time curve (per 1000 person-weeks) were 7.0 weeks and 60.8 gametocytes/microL per week, respectively, among patients with wild-type parasites, compared with 45.4 weeks (P = .016) and 1212 gametocytes/microL per week (P = .014), respectively, among those with parasites containing 1-5 dhfr/dhps mutations., Conclusions: An increased duration and density of gametocyte carriage after sulfadoxine-pyrimethamine treatment was an early indicator of drug resistance. This increased gametocytemia among patients who have primary infections with drug-resistant Plasmodium falciparum fuels the spread of resistance even before treatment failure rates increase significantly.

Background: Sulfadoxine-pyrimethamine (SP) is among the most commonly used antimalarial drugs during pregnancy, yet the pharmacokinetics of SP are unknown in pregnant women. HIV-infected (HIV(+)) women require more frequent doses of intermittent preventive therapy with SP than do HIV-uninfected (HIV(-)) women. We investigated whether this reflects their impaired immunity or an HIV-associated alteration in the disposition of SP., Methods: Seventeen pregnant HIV(-) women and 16 pregnant HIV(+) women received a dose of 1500 mg of sulfadoxine and 75 mg of pyrimethamine. Five HIV(-) and 6 HIV(+) postpartum women returned 2-3 months after delivery for another dose. The pharmacokinetics of sulfadoxine and pyrimethamine were compared between these groups., Results: HIV status did not affect the area under the curve (AUC(0-->infinity)) or the half-lives of sulfadoxine or pyrimethamine in prepartum or postpartum women, although partum status did have a significant affect on sulfadoxine pharmacokinetics. Among prepartum women, the median half-life for sulfadoxine was significantly shorter than that observed in postpartum women (148 vs 256 h; P<.001), and the median AUC(0-->infinity) was ~40% lower (22,816 vs 40,106 microg/mL/h, P<.001). HIV status and partum status did not show any significant influence on pyrimethamine pharmacokinetics., Conclusion: Pregnancy significantly modifies the disposition of SP, whereas HIV status has little influence on pharmacokinetic parameters in pregnant women.

We assessed the influence that consecutive-day blood sampling, compared with single-day blood sampling, had on polymerase chain reaction (PCR)-adjusted parasitological cure after stepwise genotyping of merozoite surface proteins 2 (msp2) and 1 (msp1) in 106 children in Tanzania who had uncomplicated falciparum malaria treated with either sulfadoxine-pyrimethamine or artemether-lumefantrine; 78 of these children developed recurrent parasitemia during the 42-day follow-up period. Initial msp2 genotyping identified 27 and 33 recrudescences by use of single- and consecutive-day sampling, respectively; in subsequent msp1 genotyping, 17 and 21 of these episodes, respectively, were still classified as recrudescences; these results indicate a similar sensitivity of the standard single-day PCR protocol--that is, 82% (27/33) and 81% (17/21), in both genotyping steps. Interpretation of PCR-adjusted results will significantly depend on methodology.

Background: The altered immune response of persons with human immunodeficiency virus (HIV) infection could result in increased rates of antimalarial treatment failure. We investigated the influence of HIV infection on the response to sulfadoxine-pyrimethamine treatment., Methods: Febrile adults with Plasmodium falciparum parasitemia were treated with sulfadoxine-pyrimethamine and were monitored for 28 days. HIV status and CD4 cell count were determined at study enrollment., Results: Of the adults enrolled in the study, 508 attended all follow-up visits, including 130 HIV-uninfected adults, 256 HIV-infected adults with a high CD4 cell count (> or =200 cells/ micro L), and 122 HIV-infected adults with a low CD4 cell count (<200 cells/ micro L). The hazard of treatment failure at day 28 of follow-up was significantly higher for HIV-infected adults with a low CD4 cell count (20.5%) than for HIV-uninfected adults (7.7%). Anemia (hemoglobin level, <110 g/L) modified the effect of HIV status on treatment failure. When we controlled for fever and parasite density, the hazard of treatment failure for HIV-infected adults with a low CD4 cell count and anemia was 3.4 times higher than that for HIV-uninfected adults (adjusted hazard ratio, 3.38; 95% confidence interval, 1.56-7.34)., Conclusions: HIV-infected persons with a low CD4 cell count and anemia have an increased risk of antimalarial treatment failure. The response to malaria treatment in HIV-infected persons must be carefully monitored. Proven measures for the control and prevention of malaria must be incorporated into the basic package of services provided by HIV/acquired immunodeficiency syndrome care and treatment programs in malarious areas.

Background: Human immunodeficiency virus (HIV)-1 infected adults with low CD4 cell count have a higher risk of malaria infection and clinical malaria. We assessed the influence that HIV-1 immune suppression has on the efficacy of antimalarial treatment in adults with uncomplicated malaria., Methods: This clinical trial included 971 Zambian adults with uncomplicated malaria. Patients were tested for HIV-1, and, if positive, a CD4 cell count was assessed. The primary outcome was recurrent parasitemia corrected by molecular genotyping within 45 days after treatment., Results: HIV-1 infection was detected in 33% (320/971) of adult patients with malaria. Treatment failure was not associated with HIV-1 infection (relative risk [RR], 1.12 [95% confidence interval {CI}, 0.82-1.53]; P=.45). HIV-1-infected patients with a CD4 cell count <300 cells/microL had an increased risk of recurrent parasitemia, compared with those with a CD4 cell count >or=300 cells/microL (RR, 2.24 [95% CI, 1.20-4.14]; P=.01). After genotyping, the risk of recrudescence was higher in HIV-1-infected patients with a CD4 cell count <300 cells/microL than in the other patients with malaria (RR, 1.67 [95% CI, 1.13-2.47]; P=.02)., Conclusion: HIV-1-infected patients with malaria with a CD4 cell count <300 cells/microL have a higher risk of experiencing a recrudescent infection, compared with those with a CD4 cell count >or=300 cells/microL or without HIV-1 infection. Trial registered at http://www.clinicaltrials.gov/; reference number NCT00304980.

Background: Recent clinical trials from Uganda have shown that the risk of failure following antimalarial therapy varies geographically. We tested the hypothesis that geographic differences in the response to therapy could be explained by differences in the prevalence of known molecular markers of drug resistance., Methods: Samples from 2084 patients treated with chloroquine (CQ) plus sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ) plus SP were tested for the presence of known molecular markers of resistance. Differences in the risk of treatment failure across 6 sites were compared, and age and complexity of infection were controlled for., Results: The prevalence of molecular markers of drug resistance was high at all of the sites: 61%-91% of patients were infected with parasites containing the pfcrt Thr-76 mutation and dhfr/dhps quintuple mutation. The risk of treatment failure decreased with increasing transmission intensity for both CQ plus SP (73% to 19%) and AQ plus SP (38% to 2%). Restricting the analyses to patients infected with parasites containing all 6 mutations of interest did not affect these trends., Conclusions: The risk of treatment failure was inversely proportional to transmission intensity and was not explained by differences in molecular markers of antimalarial drug resistance. Our findings strongly suggest that geographic differences in response to antimalarial therapy in Uganda are primarily mediated by acquired immunity associated with malaria transmission intensity, rather than by parasite factors.

Intermittent preventive treatment for malaria in infants (IPTi) is a promising malaria control strategy. However, mass preventive treatment for malaria inherently bears the risk of increasing drug resistance. Here, the effect of single-dose sulfadoxine-pyrimethamine (S-P) versus placebo on Plasmodium falciparum infection rates was assessed in 63 selected infants who were aparasitemic at enrollment. An increase in the proportion of infants with isolates exhibiting drug resistance-associated mutations was detected 3 weeks after drug application in the treatment group. S-P, in the setting of IPTi, appears to cause a parasitological rebound effect in which there is selection of drug-resistant parasites for a short period after drug clearance.

The study of molecular markers of drug resistance is particularly important in surveillance studies of drugs, such as mefloquine, that still retain efficacy in sub-Saharan Africa yet have encountered resistance elsewhere. In a recent study in Thailand, we identified amplification of the Plasmodium falciparum multidrug resistance gene 1 (pfmdr1) as being the most important predictor of in vitro drug resistance and in vivo failure of mefloquine monotherapy. Here we report amplification of pfmdr1 in >5% of patient samples from Lambarene, Gabon, collected in 1995. None of the samples collected 7 years later showed pfmdr1 amplification, suggesting that parasites with increased numbers of pfmdr1 copies have not substantially spread through the population. Nevertheless, the detection of multicopy pfmdr1 in African parasites suggests a high potential for rapid selection for resistance, implying that mefloquine use in Africa should be considered only as part of combination therapy.

Background: Malaria during pregnancy contributes to maternal anemia and low birth weight. In East Africa, several studies have demonstrated that intermittent preventive treatment (IPT) with sulfadoxine-pyrimethamine (SP) is more efficacious than weekly chloroquine (CQ) chemoprophylaxis in preventing these adverse consequences. To our knowledge, there are no published trials evaluating IPT in West Africa., Methods: We undertook a randomized controlled trial of weekly CQ chemoprophylaxis, 2-dose IPT with CQ, and 2-dose IPT with SP; 1163 women were enrolled., Results: In multivariate analyses, when compared with weekly CQ, IPT/SP was associated with a reduction in third-trimester anemia (adjusted odds ratio [AOR], 0.49; P<.001), placental parasitemia (AOR, 0.69; P=.04), and low birth weight (<2500 g) (AOR, 0.69; P=.04). The prevalence of placental infection remained unexpectedly high, even in the IPT/SP group (24.5%), possibly because of the intensity of seasonal transmission. There were no significant differences in stillbirths, spontaneous abortions, or neonatal deaths among the 3 groups., Conclusions: In Mali, IPT with SP appears more efficacious than weekly chloroquine chemoprophylaxis in preventing malaria during pregnancy. These data support World Health Organization recommendations to administer at least 2 doses of IPT during pregnancy. In intensely seasonal transmission settings in Mali, >2 doses may be required to prevent placental reinfection prior to delivery.

We investigated the evolution of drug-resistant Plasmodium falciparum in a village in eastern Sudan. The frequencies of alleles of 4 genes thought to be determinants of drug resistance were monitored from 1990 through 2001. Changes in frequencies of drug-resistance genes between wet and dry seasons were monitored from 1998 through 2000. Parasites were also typed for 3 putatively neutral microsatellite loci. No significant variation in frequencies was observed for the microsatellite loci over the whole study period or between seasons. However, genes involved in resistance to chloroquine showed consistent, significant increases in frequencies over time (rate of annual increase, 0.027/year for pfcrt and 0.018/year for pfmdr1). Genes involved in resistance to the second-line drug used in the area (Fansidar) remained at low frequencies between 1990 and 1993 but increased dramatically between 1998 and 2000, which is consistent with the advent of Fansidar usage during this period. For mutant alleles of the primary drug-resistance targets for chloroquine and pyrimethamine, higher frequencies were seen during the dry season than during the wet season. This cyclical fluctuation in drug-resistance genes most likely reflects seasonal variation in drug pressure and differences in the fitness of resistant and sensitive parasites.

Background: The target enzyme of pyrimethamine is dihydrofolate reductase (DHFR), but little is known about allelic variants of dhfr in Plasmodium vivax populations. Still less is known about associations between specific alleles and the failure of sulfadoxine/pyrimethamine (S/P) to clear the erythrocytic stages of P. vivax in vivo., Methods: We studied P. vivax dhfr mutations in 24 patients who received S/P therapy in Papua or Central Java, Indonesia, and we measured the resistance of the alleles in vitro in a dhfr yeast expression assay., Results: Fourteen (58%) of 24 patients had an inadequate therapeutic response. Two of 6 alleles that were identified were novel. One allele that expressed 4 point mutations (57L+58R+61M+117T) correlated with a high risk of therapeutic failure. The 9 patients infected by P. vivax carrying this allele proved 23 times more likely to experience early therapeutic failure, compared with patients infected by P. vivax carrying other alleles (P=.003; 95% confidence interval, 2-450). This allele also conferred high levels of pyrimethamine resistance in vitro. The experimental antifolate WR99210 inhibited the allele in this system., Conclusions: The present study identified a strong correlation between specific mutations in P. vivax dhfr and S/P treatment failure. Our results suggest that WR99210 could provide effective therapy for S/P-resistant P. vivax.

Combination antimalarial therapy may delay the spread of drug resistance, but clinical data supporting this notion are limited. For 1 year, we studied Ugandan children who were treated for uncomplicated malaria with sulfadoxine-pyrimethamine (SP), SP + amodiaquine (AQ), or SP + artesunate (AS). We compared treatment responses and the prevalence of resistance-conferring mutations of new infections with those of recrudescent infections due to parasites that survived prior treatment. Recrudescent infections were associated with the selection of SP resistance-conferring mutations in all treatment groups, but responses to repeat therapy differed. Compared with initial treatments, treatment of recrudescent infections was associated with a higher rate of treatment failure (hazard ratio [HR], 2.44; P=.01), for the SP group, but with a lower rate of treatment failure (HR, 0.40; P=.08), for the SP + AS group. Treatment failure in the SP + AQ group was uncommon, limiting the analysis of recrudescent parasites. Our results suggest that the use of combination antimalarial therapy in Africa may slow the spread of drug-resistant malaria and prolong the therapeutic life span of available treatment regimens.

In 1993, Malawi became the first African country to replace chloroquine with sulfadoxine-pyrimethamine nationwide in response to high rates of chloroquine-resistant falciparum malaria. To determine whether withdrawal of chloroquine can lead to the reemergence of chloroquine sensitivity, the prevalence of the pfcrt 76T molecular marker for chloroquine-resistant Plasmodium falciparum malaria was retrospectively measured in Blantyre, Malawi. The prevalence of the chloroquine-resistant pfcrt genotype decreased from 85% in 1992 to 13% in 2000. In 2001, chloroquine cleared 100% of 63 asymptomatic P. falciparum infections, no isolates were resistant to chloroquine in vitro, and no infections with the chloroquine-resistant pfcrt genotype were detected. A concerted national effort to withdraw chloroquine from use has been followed by a return of chloroquine-sensitive falciparum malaria in Malawi. The reintroduction of chloroquine, ideally in combination with another antimalarial drug, should be considered in areas where chloroquine resistance has declined and safe and affordable alternatives remain unavailable.

A randomized, placebo-controlled treatment trial was conducted among 546 anemic (hemoglobin concentration, 7-11 g/dL) children aged 2-36 months in an area with intense malaria transmission in western Kenya. All children used bednets and received a single dose of sulfadoxine-pyrimethamine (SP) on enrollment, followed by either intermittent preventive treatment (IPT) with SP at 4 and 8 weeks and daily iron for 12 weeks, daily iron and IPT with SP placebo, IPT and daily iron placebo, or daily iron placebo and IPT with SP placebo (double placebo). The mean hemoglobin concentration at 12 weeks, compared with that for the double-placebo group, was 1.14 g/dL (95% confidence interval [CI], 0.82-1.47 g/dL) greater for the IPT+iron group, 0.79 g/dL (95% CI, 0.46-1.10 g/dL) greater for the iron group, and 0.17 g/dL (95% CI, -0.15-0.49 g/dL) greater for the IPT group. IPT reduced the incidence of malaria parasitemia and clinic visits, but iron did not. The combination of IPT and iron supplementation was most effective in the treatment of mild anemia. Although IPT prevented malaria, the hematological benefit it added to that of a single dose of SP and bednet use was modest.

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-year-old 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 >25% 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.

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.