Malaria preventive therapy in pregnancy and its potential impact on immunity to malaria in an area of declining transmission.
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ABSTRACT: Background
Regular anti-malarial therapy in pregnancy, a pillar of malaria control, may affect malaria immunity, with therapeutic implications in regions of reducing transmission.Methods
Plasma antibodies to leading vaccine candidate merozoite antigens and opsonizing antibodies to endothelial-binding and placental-binding infected erythrocytes were quantified in pregnant Melanesian women receiving sulfadoxine-pyrimethamine (SP) with chloroquine taken once, or three courses of SP with azithromycin.Results
Malaria prevalence was low. Between enrolment and delivery, antibodies to recombinant antigens declined in both groups (p<0.0001). In contrast, median levels of opsonizing antibodies did not change, although levels for some individuals changed significantly. In multivariate analysis, the malaria prevention regimen did not influence antibody levels.Conclusion
Different preventive anti-malarial chemotherapy regimens used during pregnancy had limited impact on malarial-immunity in a low-transmission region of Papua New Guinea.Trial registrations
NCT01136850.
SUBMITTER: Teo A
PROVIDER: S-EPMC4449596 | biostudies-literature | 2015 May
REPOSITORIES: biostudies-literature
Publications
Malaria preventive therapy in pregnancy and its potential impact on immunity to malaria in an area of declining transmission.
Teo Andrew A Hasang Wina W Randall Louise M LM Unger Holger W HW Siba Peter M PM Mueller Ivo I Brown Graham V GV Rogerson Stephen J SJ
Malaria journal 20150526
<h4>Background</h4>Regular anti-malarial therapy in pregnancy, a pillar of malaria control, may affect malaria immunity, with therapeutic implications in regions of reducing transmission.<h4>Methods</h4>Plasma antibodies to leading vaccine candidate merozoite antigens and opsonizing antibodies to endothelial-binding and placental-binding infected erythrocytes were quantified in pregnant Melanesian women receiving sulfadoxine-pyrimethamine (SP) with chloroquine taken once, or three courses of SP ...[more]
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Project description:BackgroundReductions in malaria transmission decrease naturally acquired immunity, which may influence the emergence of Plasmodium falciparum artemisinin-resistant phenotypes and genotypes over time.MethodsAntibodies specific for P. falciparum antigens were determined in uncomplicated hyperparasitemic malaria patients over a 10-year period of declining malaria transmission and emerging artemisinin resistance in northwestern Thailand. We investigated the association between antibody levels and both parasite clearance time (PCt½) and artemisinin resistance-associated kelch13 genotypes over time.ResultsImmunity to P. falciparum declined prior to 2004, preceding the emergence of artemisinin resistance-associated genotypes and phenotypes (maximum mean change in antibody level per year: anti-MSP142 = -0.17; 95% confidence interval [CI] = -.31 to -.04; P = .01). In this period of declining immunity, and in the absence of kelch13 mutations, PCt½ increased. Between 2007 and 2011, levels of antibodies fluctuated, and higher antibody levels were associated with faster PCt½ (maximum yearly change in PCt½, in hours: EBA140rII = -0.39; 95% CI = -.61 to -.17; P < .001).ConclusionsUnderstanding the impact of changing transmission and immunity on the emergence of artemisinin resistance is important particularly as increased malaria control and elimination activities may enhance immunological conditions for the expansion of artemisinin-resistant P. falciparum.
| S-EPMC5853569 | biostudies-literature
Project description:BackgroundWe investigated the poorly understood impact of declining malaria transmission on maintenance of antibodies to Plasmodium falciparum merozoite antigens and infected erythrocytes (IEs), including functional immunity.MethodsIn a 3-year longitudinal cohort of 300 Kenyan children, antibodies to different AMA1 and MSP2 alleles of merozoites, IE surface antigens, and antibody functional activities were quantified.ResultsOver a period in which malaria transmission declined markedly, AMA1 and MSP2 antibodies decreased substantially; estimated half-lives of antibody duration were 0.8 year and 1-3 years, respectively. However, 69%-74% of children maintained their seropositivity to AMA1 alleles and 42%-52% to MSP2 alleles. Levels and prevalence of antimerozoite antibodies were consistently associated with increasing age and concurrent parasitemia. Antibodies promoting opsonic phagocytosis of merozoites declined rapidly (half-life, 0.15 years). In contrast, complement-fixing antibodies to merozoites did not decline and antibodies to IE surface antigens expressing virulent phenotypes were much better maintained (half-life, 4-10 years).ConclusionsA decline in malaria transmission is associated with reduction in naturally acquired immunity. However, loss of immunity is not universal; some key functional responses and antibodies to IEs were better maintained and these may continue to provide some protection. Findings have implications for malaria surveillance and control measures and informing vaccine development.
| S-EPMC5853596 | biostudies-literature
Project description:Malaria during pregnancy results in adverse outcomes for mothers and infants. Intermittent preventive treatment (IPT) with sulphadoxine-pyrimethamine (SP) is the primary intervention aimed at reducing malaria infection during pregnancy. Although submicroscopic infection is common during pregnancy and at delivery, its impact throughout pregnancy on the development of placental malaria and adverse pregnancy outcomes has not been clearly established.Quantitative PCR was used to detect submicroscopic infections in pregnant women enrolled in an observational study in Blantyre, Malawi to determine their effect on maternal, foetal and placental outcomes. The ability of SP to treat and prevent submicroscopic infections was also assessed.2,681 samples from 448 women were analysed and 95 submicroscopic infections were detected in 68 women, a rate of 0.6 episodes per person-year of follow-up. Submicroscopic infections were most often detected at enrolment. The majority of women with submicroscopic infections did not have a microscopically detectable infection detected during pregnancy. Submicroscopic infection was associated with placental malaria even after controlling for microscopically detectable infection and was associated with decreased maternal haemoglobin at the time of detection. However, submicroscopic infection was not associated with adverse maternal or foetal outcomes at delivery. One-third of women with evidence of placental malaria did not have documented peripheral infection during pregnancy. SP was moderately effective in treating submicroscopic infections, but did not prevent the development of new submicroscopic infections in the month after administration.Submicroscopic malaria infection is common and occurs early in pregnancy. SP-IPT can clear some submicroscopic infections but does not prevent new infections after administration. To effectively control pregnancy-associated malaria, new interventions are required to target women prior to their first antenatal care visit and to effectively treat and prevent all malaria infections.
| S-EPMC4110536 | biostudies-other
Project description:We investigated the effectiveness of routine preventive measures for anemia in Beninese pregnant women during pregnancy. Anemia (hemoglobin < 110 g/L) was common: 68.3% at first antenatal visit (ANV1), 64.7% at second antenatal visit (ANV2), and 40.6% at delivery. Parasitic infections and nutritional deficiencies were the most preventable causes. After intermittent preventive treatment (IPTp) and antihelminthic treatments, malaria prevalence decreased from 15.1% (ANV1) to 4.0% (ANV2) and increased again to 9.6% at delivery. Helminth infections dropped from 11.1% (ANV1) to 7.2% (ANV2) and 2.4% at delivery. Malaria was associated with lower mean hemoglobin on ANV1 and delivery, and iron deficiency was associated with lower mean hemoglobin on ANV1 and ANV2. IPTp and antihelminthic treatments were efficacious to clear parasitic infections and improve hematologic status, whereas the effectiveness of daily iron and folic acid supplements to correct iron and folate deficiencies and decrease anemia was less marked, possibly because of lack of compliance.
| S-EPMC3583320 | biostudies-literature
Project description:Coendemicity between the human immunodeficiency virus (HIV) and Plasmodium parasites, the causative agents of acquired immunodeficiency syndrome (AIDS) and malaria, respectively, occurs in several regions around the world. Although the impact of the interaction between these two organisms is not well understood, it is thought that the outcome of either disease may be negatively influenced by coinfection. Therefore, it is important to understand how current first-line antiretroviral therapies (ART) might impact Plasmodium infection in these regions. Here, we describe the effect of 18 antiretroviral compounds and of first-line ART on the blood and sporogonic stages of Plasmodium berghei in vitro and in vivo. We show that the combination zidovudine + lamivudine + lopinavir/ritonavir (LPV/r), employed as first-line HIV treatment in the field, has a strong inhibitory activity on the sporogonic stages of P. berghei and that several non-nucleoside reverse transcriptase inhibitors (NNRTI) have a moderate effect on this stage of the parasite's life cycle. Our results expose the effect of current first-line ART on Plasmodium infection and identify potential alternative therapies for HIV/AIDS that might impact malaria transmission.
| S-EPMC6993566 | biostudies-literature
Project description:BackgroundTreatment of asymptomatic individuals, regardless of their malaria infection status, with regularly spaced therapeutic doses of antimalarial drugs has been proposed as a method for reducing malaria morbidity and mortality. This strategy, called intermittent preventive treatment (IPT), is currently employed for pregnant women and is being studied for infants (IPTi) as well. As with any drug-based intervention strategy, it is important to understand how implementation may affect the spread of drug-resistant parasites. This is a difficult issue to address experimentally because of the limited size and duration of IPTi trials as well as the intractability of distinguishing the spread of resistance due to conventional treatment of malaria episodes versus that due to IPTi when the same drug is used in both contexts.Methods and findingsUsing a mathematical model, we evaluated the possible impact of treating individuals with antimalarial drugs at regular intervals regardless of their infection status. We translated individual treatment strategies and drug pharmacokinetics into parasite population dynamic effects and show that immunity, treatment rate, drug decay kinetics, and presumptive treatment rate are important factors in the spread of drug-resistant parasites. Our model predicts that partially resistant parasites are more likely to spread in low-transmission areas, but fully resistant parasites are more likely to spread under conditions of high transmission, which is consistent with some epidemiological observations. We were also able to distinguish between spread of resistance due to treatment of symptomatic infections and that due to IPTi. We showed that IPTi could accelerate the spread of resistant parasites, but this effect was only likely to be significant in areas of low or unstable transmission.ConclusionsThe results presented here demonstrate the importance of considering both the half-life of a drug and the existing level of resistance when choosing a drug for IPTi. Drugs to which little or no resistance exists are not advisable for IPT in high-transmission areas, but IPTi is not likely to significantly impact the spread of highly resistant parasites in areas where partial resistance is already established. IPTi is more likely to accelerate the spread of resistance in high-transmission areas than is IPT in adults (i.e., pregnant women).
| S-EPMC1440294 | biostudies-literature
Project description:ObjectiveTo evaluate the effects of intermittent preventive treatment for malaria in infants (IPTi) with sulfadoxine-pyrimethamine in an area of intense, seasonal transmission.DesignCluster randomised placebo controlled trial, with 96 clusters allocated randomly to sulfadoxine-pyrimethamine or placebo in blocks of eight.InterventionsChildren received sulfadoxine-pyrimethamine or placebo and one month of iron supplementation when they received DPT-2, DPT-3, or measles vaccinations and at 12 months of age.Main outcome measuresIncidence of malaria and of anaemia determined through passive case detection.Results89% (1103/1242) of children in the placebo group and 88% (1088/1243) in the IPTi group completed follow-up to 24 months of age. The protective efficacy of IPTi against all episodes of malaria was 24.8% (95% confidence interval 14.3% to 34.0%) up to 15 months of age. IPTi had no protective effect against malaria between 16 and 24 months of age (protective efficacy -4.9%, -21.3% to 9.3%). The incidence of high parasite density malaria (> or = 5000 parasites/mul) was higher in the IPTi group than in the placebo group between 16 and 24 months of age (protective efficacy -19.5%, -39.8% to -2.2%). IPTi reduced hospital admissions with anaemia by 35.1% (10.5% to 52.9%) up to 15 months of age. IPTi had no significant effect on anaemia between 16 and 24 months of age (protective efficacy -6.4%, -76.8% to 35.9%). The relative risk of death up to 15 months of age in the IPTi group was 1.26 (95% confidence interval 0.81 to 1.96; P = 0.31), and from 16 to 24 months it was 1.28 (0.77 to 2.14; P = 0.35).ConclusionsIntermittent preventive treatment for malaria with sulfadoxine-pyrimethamine can reduce malaria and anaemia in infants even in seasonal, high transmission areas, but concern exists about possible rebound in the incidence of malaria in the second year of life.
| S-EPMC1239974 | biostudies-literature
Project description:Owing to increasing sulfadoxine-pyrimethamine (SP) resistance in sub-Saharan Africa, monitoring the effectiveness of intermittent preventive therapy in pregnancy (IPTp) with SP is crucial.Between 2009 and 2013, both the efficacy of IPTp-SP at clearing existing peripheral malaria infections and the effectiveness of IPTp-SP at reducing low birth weight (LBW) were assessed among human immunodeficiency virus-uninfected participants in 8 sites in 6 countries. Sites were classified as high, medium, or low resistance after measuring parasite mutations conferring SP resistance. An individual-level prospective pooled analysis was conducted.Among 1222 parasitemic pregnant women, overall polymerase chain reaction-uncorrected and -corrected failure rates by day 42 were 21.3% and 10.0%, respectively (39.7% and 21.1% in high-resistance areas; 4.9% and 1.1% in low-resistance areas). Median time to recurrence decreased with increasing prevalence of Pfdhps-K540E. Among 6099 women at delivery, IPTp-SP was associated with a 22% reduction in the risk of LBW (prevalence ratio [PR], 0.78; 95% confidence interval [CI], .69-.88; P < .001). This association was not modified by insecticide-treated net use or gravidity, and remained significant in areas with high SP resistance (PR, 0.81; 95% CI, .67-.97; P = .02).The efficacy of SP to clear peripheral parasites and prevent new infections during pregnancy is compromised in areas with >90% prevalence of Pfdhps-K540E. Nevertheless, in these high-resistance areas, IPTp-SP use remains associated with increases in birth weight and maternal hemoglobin. The effectiveness of IPTp in eastern and southern Africa is threatened by further increases in SP resistance and reinforces the need to evaluate alternative drugs and strategies for the control of malaria in pregnancy.
| S-EPMC4762476 | biostudies-literature
Project description:Background & aimsLow iron stores may protect from malaria infection, therefore improving iron stores in early pregnancy in line with current recommendations could increase malaria susceptibility. To test this hypothesis we compared iron biomarkers and red cell indices in nulliparae and primigravidae who participated in a randomized controlled trial of long-term weekly iron supplementation.MethodsCross-sectional and longitudinal data analysis from a randomized controlled trial of long-term weekly iron supplementation in rural Burkina Faso. Malaria parasitaemia was monitored and biomarkers and red cell indices measured at study end-points: plasma ferritin, transferrin receptor (sTfR), zinc protoporphyrin, hepcidin, sTfR/log10 ferritin ratio, body iron, haemoglobin, red cell distribution width; mean corpuscular haemoglobin concentration/volume, and C-reactive protein. Correlation coefficients between biomarkers and red cell indices were determined. A regression correction approach based on ferritin was used to estimate iron body stores, allowing for inflammation. Body iron differences were compared between nulliparae and primigravidae, and the association determined of iron biomarkers and body iron stores with malaria.ResultsIron and haematological indices of 972 nulliparae (mean age 16.5 years) and 314 primigravidae (median gestation 18 weeks) were available. Malaria prevalence was 54.0% in primigravidae and 41.8% in nulliparae (relative risk 1.28, 95% CI 1.13-1.45, P < 0.001), anaemia prevalence 69.7% and 43.4% (P < 0.001), and iron deficient erythropoiesis (low body iron) 8.0% and 11.7% (P = 0.088) respectively. Unlike other biomarkers the sTfR/log10 ferritin ratio showed no correlation with inflammation as measured by CRP. Most biomarkers indicated reduced iron deficiency in early pregnancy, with the exception of haemoglobin. Body iron increased by 0.6-1.2 mg/kg in early gestation, did not differ by malaria status in nulliparae, but was higher in primigravidae with malaria (6.5 mg/kg versus 5.0 mg/kg; relative risk 1.53, 95% CI 0.67-2.38, P < 0.001).ConclusionIn primigravidae, early pregnancy haemoglobin was not a good indicator of requirement for iron supplementation, which could be detrimental given the association of better iron status with increased malaria infection.Trial registrationclinicaltrials.gov:NCT01210040. Until placed in a public repository, data relating to the current study can be requested from the corresponding author and will be made available following an end user data agreement and sponsor approval.
| S-EPMC6660428 | biostudies-literature
Project description:Dihydroartemisinin-piperaquine (DP) is a long-acting artemisinin combination treatment that provides effective chemoprevention and has been proposed as an alternative antimalarial drug for intermittent preventive therapy in pregnancy (IPTp). Several pharmacokinetic studies have shown that dose adjustment may not be needed for the treatment of malaria in pregnancy with DP. However, there are limited data on the optimal dosing for IPTp. This study aimed to evaluate the population pharmacokinetics of piperaquine given as IPTp in pregnant women. Pregnant women were enrolled in clinical trials conducted in Kenya and Indonesia and treated with standard 3-day courses of DP, administered in 4- to 8-week intervals from the second trimester until delivery. Pharmacokinetic blood samples were collected for piperaquine drug measurements before each treatment round, at the time of breakthrough symptomatic malaria, and at delivery. Piperaquine population pharmacokinetic properties were investigated using nonlinear mixed-effects modeling with a prior approach. In total, data from 366 Kenyan and 101 Indonesian women were analyzed. The pharmacokinetic properties of piperaquine were adequately described using a flexible transit absorption (n = 5) followed by a three-compartment disposition model. Gestational age did not affect the pharmacokinetic parameters of piperaquine. After three rounds of monthly IPTp, 9.45% (95% confidence interval [CI], 1.8 to 26.5%) of pregnant women had trough piperaquine concentrations below the suggested target concentration (10.3 ng/ml). Translational simulations suggest that providing the full treatment course of DP at monthly intervals provides sufficient protection to prevent malaria infection. Monthly administration of DP has the potential to offer optimal prevention of malaria during pregnancy. (This study has been registered at ClinicalTrials.gov under identifier NCT01669941 and in the ISRCTN under number ISRCTN34010937.).
| S-EPMC8092554 | biostudies-literature