A multi-center, open-label trial to compare the efficacy and pharmacokinetics of Artemether-Lumefantrine in children with severe acute malnutrition versus children without severe acute malnutrition: study protocol for the MAL-NUT study

BACKGROUND:Malnutrition and malaria frequently coexist in sub-Saharan African countries. Studies on efficacy of antimalarial treatments usually follow the WHO standardized protocol in which severely malnourished children are systematically excluded.Few studies have assessed the efficacy of chloroquine, sulfadoxine-pyrimethamine and quinine in severe acute malnourished children. Overall, efficacy of these treatments appeared to be reduced, attributed to lower immunity and for some antimalarials altered pharmacokinetic profiles and lower drug concentrations. However, similar research on the efficacy and pharmacokinetic profiles of artemisinin-combination therapies (ACTs) and especially artemether-lumefantrine in malnourished children is currently lacking.The main objective of this study is to assess whether artemether-lumefantrine is less efficacious in children suffering from severe acute malnutrition (SAM) compared to non-SAM children, and if so, to what extent this can be attributed to a sub-optimal pharmacokinetic profile.METHODS/DESIGN:In two sites, Ouelessebougou, Mali and Maradi, Niger, children with uncomplicated microscopically-confirmed P. falciparum malaria aged between 6 and 59 months will be enrolled. Two non-SAM children will be enrolled after the enrolment of each SAM case. Children with severe manifestations of malaria or complications of acute malnutrition needing intensive treatment will be excluded.Treatment intakes will be supervised and children will be followed-up for 42 days, according to WHO guidance for surveillance of antimalarial drug efficacy. Polymerase Chain Reaction genotyping will be used to distinguish recrudescence from re-infection. SAM children will also benefit from the national nutritional rehabilitation program.Outcomes will be compared between the SAM and non-SAM populations. The primary outcome will be adequate clinical and parasitological response at day 28 after PCR correction, estimated by Kaplan-Meier analysis. To assess the pharmacokinetic profile of lumefantrine, a sparse sampling approach will be used with randomized allocation of sampling times (5 per child). A total of 180 SAM children and 360 non-SAM children will be recruited during the 2013 and 2014 malaria seasons.DISCUSSION:This study will provide important information that is currently lacking on the effect of SAM on therapeutic efficacy and pharmacokinetic profile of artemether-lumefantrine. If it shows lower therapeutic efficacy and decreased lumefantrine concentrations, it would inform dose optimization studies in SAM children.TRIAL REGISTRATION:ClinicalTrials.gov: NCT0195890

Integrating pediatric TB services into child healthcare services in Africa: study protocol for the INPUT cluster-randomized stepped wedge trial

Background Tuberculosis is among the top-10 causes of mortality in children with more than 1 million children suffering from TB disease annually worldwide. The main challenge in young children is the difficulty in establishing an accurate diagnosis of active TB. The INPUT study is a stepped-wedge cluster-randomized intervention study aiming to assess the effectiveness of integrating TB services into child healthcare services on TB diagnosis capacities in children under 5 years of age. Methods Two strategies will be compared: i) The standard of care, offering pediatric TB services based on national standard of care; ii) The intervention, with pediatric TB services integrated into child healthcare services: it consists of a package of training, supportive supervision, job aids, and logistical support to the integration of TB screening and diagnosis activities into pediatric services. The design is a cluster-randomized stepped-wedge of 12 study clusters in Cameroon and Kenya. The sites start enrolling participants under standard-of-care and will transition to the intervention at randomly assigned time points. We enroll children aged less than 5 years with a presumptive diagnosis of TB after obtaining caregiver written informed consent. The participants are followed through TB diagnosis and treatment, with clinical information prospectively abstracted from their medical records. The primary outcome is the proportion of TB cases diagnosed among children < 5 years old attending the child healthcare services. Secondary outcomes include: number of children screened for presumptive active TB; diagnosed; initiated on TB treatment; and completing treatment. We will also assess the cost-effectiveness of the intervention, its acceptability among health care providers and users, and fidelity of implementation. Discussion Study enrolments started in May 2019, enrolments will be completed in October 2020 and follow up will be completed by June 2021. The study findings will be disseminated to national, regional and international audiences and will inform innovative approaches to integration of TB screening, diagnosis, and treatment initiation into child health care services.publishedVersio

Is chloroquine chemoprophylaxis still effective to prevent low birth weight? Results of a study in Benin

BACKGROUND: In areas of stable transmission, malaria during pregnancy is associated with severe maternal and foetal outcomes, especially low birth weight (LBW). To prevent these complications, weekly chloroquine (CQ) chemoprophylaxis is now being replaced by intermittent preventive treatment with sulfadoxine-pyrimethamine in West Africa. The prevalence of placental malaria and its burden on LBW were assessed in Benin to evaluate the efficacy of weekly CQ chemoprophylaxis, prior to its replacement by intermittent preventive treatment. METHODS: In two maternity clinics in Ouidah, an observational study was conducted between April 2004 and April 2005. At each delivery, placental blood smears were examined for malaria infection and women were interviewed on their pregnancy history including CQ intake and dosage. CQ was measured in the urine of a sub-sample (n = 166). Multiple logistic and linear regression were used to assess factors associated with LBW and placental malaria. RESULTS: Among 1090 singleton live births, prevalence of placental malaria and LBW were 16% and 17% respectively. After adjustment, there was a non-significant association between placental malaria and LBW (adjusted OR = 1.43; P = 0.10). Multiple linear regression showed a positive association between placental malaria and decreased birth weight in primigravidae. More than 98% of the women reported regular chemoprophylaxis and CQ was detectable in 99% of urine samples. Protection from LBW was high in women reporting regular CQ prophylaxis, with a strong duration-effect relationship (test for linear trend: P < 0,001). CONCLUSION: Despite high parasite resistance and limited effect on placental malaria, a CQ chemoprophylaxis taken at adequate doses showed to be still effective in reducing LBW in Benin

Early biting and insecticide resistance in the malaria vector Anopheles might compromise the effectiveness of vector control intervention in Southwestern Uganda.

BACKGROUND: Southwestern Uganda has high malaria heterogeneity despite moderate vector control and other interventions. Moreover, the early biting transmission and increased resistance to insecticides might compromise strategies relying on vector control. Consequently, monitoring of vector behaviour and insecticide efficacy is needed to assess the effectiveness of strategies aiming at malaria control. This eventually led to an entomological survey in two villages with high malaria prevalence in this region. METHODS: During rainy, 2011 and dry season 2012, mosquitoes were collected in Engari and Kigorogoro, Kazo subcounty, using human landing collection, morning indoor resting collection, pyrethrum spray collection and larval collection. Circumsporozoite protein of Plasmodium falciparum sporozoites in female Anopheles mosquitoes was detected using ELISA assay. Bioassays to monitor Anopheles resistance to insecticides were performed. RESULTS: Of the 1,021 female Anopheles species captured, 62% (632) were Anopheles funestus and 36% (371) were Anopheles gambiae s.l. The most common species were Anopheles gambiae s.l. in Engari (75%) and A. funestus in Kigorogoro (83%). Overall, P. falciparum prevalence was 2.9% by ELISA. The daily entomological inoculation rates were estimated at 0.17 and 0.58 infected bites/person/night during rainy and dry season respectively in Engari, and 0.81 infected bites/person/night in Kigorogoro during dry season. In both areas and seasons, an unusually early evening biting peak was observed between 6 - 8 p.m. In Engari, insecticide bioassays showed 85%, 34% and 12% resistance to DDT during the rainy season, dry season and to deltamethrin during the dry season, respectively. In Kigorogoro, 13% resistance to DDT and to deltamethrin was recorded. There was no resistance observed to bendiocarb and pirimiphos methyl. CONCLUSIONS: The heterogeneity of mosquito distribution, entomological indicators and resistance to insecticides in villages with high malaria prevalence highlight the need for a long-term vector control programme and monitoring of insecticide resistance in Uganda. The early evening biting habits of Anopheles combined with resistance to DDT and deltamethrin observed in this study suggest that use of impregnated bed nets alone is insufficient as a malaria control strategy, urging the need for additional interventions in this area of high transmission

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Taha Toros Arşivi, Dosya No: 220-Kaptanzade Ali Rıza Be

Prévention du paludisme chez la femme enceinte infectée par le VIH

Chez la femme enceinte séropositive, deux stratégies préventives du paludisme sont recommandées : soit une prophylaxie par cotrimoxazole (CTX) si la femme doit la recevoir pour son VIH, soit un traitement préventif intermittent (TPI). L essai PACOME avait pour objectif d évaluer l efficacité du CTX comparativement à celle du TPI par méfloquine (MQ) au Bénin. Deux essais de non infériorité ont été menés en parallèle : Les femmes éligibles au CTX pour leur VIH recevaient soit le CTX seul, soit l association CTX et TPI MQ (essai B). Les autres recevaient soit le CTX seul, soit le TPI MQ seul (essai H). Le critère de jugement principal était la prévalence de l infection palustre placentaire. 292 femmes ont été incluses dans l essai B et 140 dans l essai H. Une infection placentaire a été retrouvée dans chaque essai, sous CTX seul. La différence de prévalence de l infection placentaire était 0,9% dans l essai B (borne supérieure de l IC inférieure à 5%). Dans l essai H, elle était de 1,8% et la faible puissance ne permettait pas de conclure. Une seule réaction cutanée grave a été observée sous CTX. Des effets secondaires modérés (vertiges, vomissements) sont survenus chez 57% des femmes après prise de MQ. Cette prévalence n était pas supérieure à celle observée chez des femmes enceintes séronégatives. Ainsi, le CTX possède une efficacité antipaludique suffisante pour être proposé comme unique moyen de prévention chez la femme éligible à cette prophylaxie pour son VIH. Le TPI par MQ a également montré sa grande efficacité dans cette population, il reste une alternative en cas d'émergences de résistances au CTXCotrimoxazole (CTX) prophylaxis given to HIV-infected pregnant women (PW) for the prevention of opportunistic infections is assumed to also protect them against malaria. Alternatively, an intermittent preventive treatment (IPTp) is recommended. The PACOME trial evaluated the efficacy of CTX versus MQ IPTp in HIV-positive PW, in Benin. Two subtrials were designed: PW eligible to CTX were randomly assigned to daily CTX, or the association of daily CTX with MQ IPTp (trial A). For non eligible pregnant women, the two treatment groups were CTX prophylaxis and MQ IPTp alone (trial B). The target sample size to judge treatment efficacy as placental malaria prevalence by microscopy was 284 in each sub trial 292 PW were enrolled in trial A and 140 in trial B. Two placental infections were observed, one in each sub trial, both receiving CTX alone. In trial A, the difference was 0.9% (upper bound of the confidence interval <5%). In trial B, the difference was 1.8%, but insufficient power did not allow conclusions. Minor adverse reactions (dizziness, vomiting) following MQ intake were reported by 57% of PW. For PW eligible to CTX prophylaxis for their HIV, this trial demonstrated that CTX provided sufficient protection against placental malaria. CTX can therefore be recommended for malaria prevention in these women. The PACOME trial also demonstrated that MQ IPTp had a high antimalarial efficacy. In the context of rapid progression of parasite resistance to sulfa drugs, a loss of efficacy of CTX is expected soon or late. In this perspective, MQ IPTp remains a good alternative in HIV-infected PWPARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

Protective antibodies against placental malaria and poor outcomes during pregnancy, Benin

Placental malaria is caused by Plasmodium falciparum infected erythrocytes that bind to placental tissue. Binding is mediated by VAR2CSA, a parasite antigen coded by the var gene, which interacts with chondroitin sulfate A (CSA). Consequences include maternal anemia and fetal growth retardation. Antibody-mediated immunity to placental malaria is acquired during successive pregnancies, but the target of VAR2CSA-specific protective antibodies is unclear. We assessed VAR2CSA-specific antibodies in pregnant women and analyzed their relationships with protection against placental infection, preterm birth, and low birthweight. Antibody responses to the N-terminal region of VAR2CSA during early pregnancy were associated with reduced risks for infections and low birthweight. Among women infected during pregnancy, an increase in CSA binding inhibition was associated with reduced risks for placental infection, preterm birth, and low birthweight. These data suggest that antibodies against VAR2CSA N-terminal region mediate immunity to placental malaria and associated outcomes. Our results validate current vaccine development efforts with VAR2CSA N-terminal constructs

Insights into circulating cytokine dynamics during pregnancy in HIV-infected beninese exposed to Plasmodium falciparum malaria

We investigated the circulating plasma levels of Th1- (Interleukin-2 [IL-2], tumor necrosis factor-alpha [TNF-alpha], interferon-gamma [IFN-gamma]) and Th2-type (1L-4, IL-5, IL-10) cytokines in human immunodeficiency virus (HIV)-infected pregnant women living in a malaria-endemic area. We analyzed samples from 200 pregnant women included in the prevention of pregnancy-associated malaria in HIV-infected women: cotrimoxazole prophylaxis versus mefloquine (PACOME) clinical trial who were followed until delivery. Cytokine concentrations were measured by flow cytometry-based multiplex bead array. Significantly elevated levels of IL-10 and lower levels of TNF-alpha were observed at delivery compared with inclusion (P = 0.005). At inclusion, the presence of circulating 1FN-gamma, a higher CD4(+) T cell count and having initiated intermittent preventive treatment of malaria with sulfadoxine pyrimethamine (SP-IPTp) were all associated with a lower likelihood of Plasmodium falciparum infection. At delivery, the inverse relationship between the presence of infection and circulating IFN-gamma persisted, although there was a positive association between the likelihood of infection and the presence of circulating TNF-alpha. Initiation of antiretroviral therapy was associated with elevated IL-5 production. Consistent with our own and others' observations in HIV seronegative subjects, this study shows circulating IL-10 to be a marker of infection with P. falciparum during pregnancy even in HIV-infected women, although plasma IFN-gamma may be a marker of anti-malarial protection in such women