Parasitic infections during pregnancy : birth outcomes and immunological changes

  Low birth weight including preterm birth and intrauterine growth retardation, remains important in sub-Saharan Africa and particularly highly prevalent in Gabon. Among the risk factors of low birth weight in sub-Saharan Africa are very young maternal age, first pregnancy, poor gestational nutrition and small stature of the mother. In Gabon, besides malaria, the other two major parasitic infections namely urogenital schistosomiasis and the filarial infection Loa loa, are common in pregnant women. Maternal schistosomiasis like malaria showed to be associated with higher proportions of low birth weight babies. Mefloquine as an alternative preventive treatment, despite showing no difference with sulphadoxine – pyrimethamine in preventing low birth weight, was however more effective in preventing malaria infection and anaemia. Mefloquine administered for the prevention of malaria was effective against concomitant urogenital schistosomiasis, suggesting that mefloquine could seriously be considered as a combined intervention for both malaria and schistosomiasis during pregnancy, and an alternative to praziquantel. Maternal infection with L. loa was associated with expansion in the neonatal cord blood of functionally activate Tregs that kept Th1 and Th17 immune responses in check, providing some insights on the impact of in utero exposure on the offspring’s development and health.  Cermel, EDCTPLUMC / Geneeskund

Prospective evaluation of artemether-lumefantrine for the treatment of non-falciparum and mixed-species malaria in Gabon

Background: The recommendation of artemisinin combination therapy (ACT) as first-line treatment for uncomplicated falciparum malaria is supported by a plethora of high quality clinical trials. However, their recommendation for the treatment of mixed-species malaria and the large-scale use for the treatment of non-falciparum malaria in endemic regions is based on anecdotal rather than systematic clinical evidence. Methods: This study prospectively observed the efficacy of artemether-lumefantrine for the treatment of uncomplicated non-falciparum or mixed-species malaria in two routine district hospitals in the Central African country of Gabon. Results: Forty patients suffering from uncomplicated Plasmodium malariae, Plasmodium ovale or mixed-species malaria (including Plasmodium falciparum) presenting at the hospital received artemether-lumefantrine treatment and were followed up. All evaluable patients (n = 38) showed an adequate clinical and parasitological response on Day 28 after oral treatment with artemether-lumefantrine (95% confidence interval: 0.91,1). All adverse events were of mild to moderate intensity and completely resolved by the end of study. Conclusions: This first systematic assessment of artemether-lumefantrine treatment for P. malariae, P. ovale and mixed-species malaria demonstrated a high cure rate of 100% and a favourable tolerability profile, and thus lends support to the practice of treating non-falciparum or mixed-species malaria, or all cases of malaria without definite species differentiation, with artemether-lumefantrine in Gabon. Trial Registration: ClinicalTrials.gov Identifier: NCT0072577

Species and genotype diversity of Plasmodium in malaria patients from Gabon analysed by next generation sequencing

Background Six Plasmodium species are known to naturally infect humans. Mixed species infections occur regularly but morphological discrimination by microscopy is difficult and multiplicity of infection (MOI) can only be evaluated by molecular methods. This study investigated the complexity of Plasmodium infections in patients treated for microscopically detected non- falciparum or mixed species malaria in Gabon. Methods Ultra-deep sequencing of nucleus (18S rRNA), mitochondrion, and apicoplast encoded genes was used to evaluate Plasmodium species diversity and MOI in 46 symptomatic Gabonese patients with microscopically diagnosed non-falciparum or mixed species malaria. Results Deep sequencing revealed a large complexity of coinfections in patients with uncomplicated malaria, both on species and genotype levels. Mixed infections involved up to four parasite species (Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale curtisi, and P. ovale wallikeri). Multiple genotypes from each species were determined from the asexual 18S rRNA gene. 17 of 46 samples (37%) harboured multiple genotypes of at least one Plasmodium species. The number of genotypes per sample (MOI) was highest in P. malariae (n = 4), followed by P. ovale curtisi (n = 3), P. ovale wallikeri (n = 3), and P. falciparum (n = 2). The highest combined genotype complexity in samples that contained mixed-species infections was seven. Conclusions Ultra- deep sequencing showed an unexpected breadth of Plasmodium species and within species diversity in clinical samples. MOI of P. ovale curtisi, P. ovale wallikeri and P. malariae infections were higher than anticipated and contribute significantly to the burden of malaria in Gabon

A thirteen-year analysis of Plasmodium falciparum populations reveals high conservation of the mutant pfcrt haplotype despite the withdrawal of chloroquine from national treatment guidelines in Gabon

<p>Abstract</p> <p>Background</p> <p>Chloroquine resistance (CR) decreased after the removal of chloroquine from national treatment guidelines in Malawi, Kenia and Tanzania. In this investigation the prevalence of the chloroquine resistance (CQR) conferring mutant <it>pfcrt </it>allele and its associated chromosomal haplotype were determined before and after the change in Gabonese national treatment guidelines from chloroquine (CQ) to artesunate plus amodiaquine (AQ) in 2003.</p> <p>Methods</p> <p>The prevalence of the wild type <it>pfcrt </it>allele was assessed in 144 isolates from the years 2005 - 07 by PCR fragment restriction digest and direct sequencing. For haplotype analysis of the chromosomal regions flanking the <it>pfcrt </it>locus, microsatellite analysis was done on a total of 145 isolates obtained in 1995/96 (43 isolates), 2002 (47 isolates) and 2005 - 07 (55 isolates).</p> <p>Results</p> <p>The prevalence of the mutant <it>pfcrt </it>allele decreased from 100% in the years 1995/96 and 2002 to 97% in 2005 - 07. Haplotype analysis showed that in 1995/96 79% of the isolates carried the same microsatellite alleles in a chromosomal fragment spanning 39 kb surrounding the <it>pfcrt </it>locus. In 2002 and 2005 - 07 the prevalence of this haplotype was 62% and 58%, respectively. <it>Pfcrt </it>haplotype analysis showed that all wild type alleles were CVMNK.</p> <p>Conclusion</p> <p>Four years after the withdrawal of CQ from national treatment guidelines the prevalence of the mutant <it>pfcrt </it>allele remains at 97%. The data suggest that the combination of artesunate plus AQ may result in continued selection for the mutant <it>pfcrt </it>haplotype even after discontinuance of CQ usage.</p

Phase I randomized dose-ascending placebo-controlled trials of ferroquine - a candidate anti-malarial drug - in adults with asymptomatic Plasmodium falciparum infection

<p>Abstract</p> <p>Background</p> <p>The development and spread of drug resistant <it>Plasmodium falciparum </it>strains is a major concern and novel anti-malarial drugs are, therefore, needed. Ferroquine is a ferrocenic derivative of chloroquine with proven anti-malarial activity against chloroquine-resistant and -sensitive <it>P. falciparum </it>laboratory strains.</p> <p>Methods</p> <p>Adult young male aged 18 to 45 years, asymptomatic carriers of <it>P. falciparum</it>, were included in two-dose escalation, double-blind, randomized, placebo-controlled Phase I trials, a single dose study and a multiple dose study aiming to evaluate oral doses of ferroquine from 400 to 1,600 mg.</p> <p>Results</p> <p>Overall, 54/66 patients (40 and 26 treated in the single and multiple dose studies, respectively) experienced at least one adverse event, 15 were under placebo. Adverse events were mainly gastrointestinal symptoms such as abdominal pain (16), diarrhoea (5), nausea (13), and vomiting (9), but also headache (11), and dizziness (5). A few patients had slightly elevated liver parameters (10/66) including two patients under placebo. Moderate changes in QTc and morphological changes in T waves were observed in the course of the study. However, no adverse cardiac effects with clinical relevance were observed.</p> <p>Conclusions</p> <p>These phase I trials showed that clinically, ferroquine was generally well-tolerated up to 1,600 mg as single dose and up to 800 mg as repeated dose in asymptomatic young male with <it>P. falciparum </it>infection. Further clinical development of ferroquine, either alone or in combination with another anti-malarial, is highly warranted and currently underway.</p

Loa loa Infection in Pregnant Women, Gabon

Loa loa, the African eye worm, is a filarial pathogen of Central African rainforest regions. As of 2013, it had affected an estimated 2–3 million persons in Central Africa (1,2). Adult worm migrations in humans may intermittently cause Calabar swelling, and microfilariae are commonly found in blood and body fluids. Loiasis is a chronic infection persisting for many years; a considerable proportion of women in loiasis-endemic regions are infected during gestation. To date, the epidemiology of loiasis in pregnant women has not been investigated, and the effects of loiasis on maternal and fetal health outcomes are unknown. We investigated the epidemiology of loiasis in a cohort of pregnant women participating in a drug trial for preventing malaria during pregnancy

High prevalence of dhfr triple mutant and correlation with high rates of sulphadoxine-pyrimethamine treatment failures in vivo in Gabonese children

BACKGROUND: Drug resistance contributes to the global malaria burden. Plasmodium falciparum dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) polymorphisms confer resistance to sulphadoxine-pyrimethamine (SP). METHODS: The study assessed the frequency of SP resistance-conferring polymorphisms in Plasmodium falciparum-positive samples from two clinical studies in Lambaréné. Their role on treatment responses and transmission potential was studied in an efficacy open-label clinical trial with a 28-day follow-up in 29 children under five with uncomplicated malaria. RESULTS: SP was well tolerated by all subjects in vivo. Three subjects were excluded from per-protocol analysis. PCR-corrected, 12/26 (46%) achieved an adequate clinical and parasitological response, 13/26 (50%) were late parasitological failures, while 1/26 (4%) had an early treatment failure, resulting in early trial discontinuation. Of 106 isolates, 98 (92%) carried the triple mutant dhfr haplotype. Three point mutations were found in dhps in a variety of haplotypic configurations. The 437G + 540E double mutant allele was found for the first time in Gabon. CONCLUSIONS: There is a high prevalence of dhfr triple mutant with some dhps point mutations in Gabon, in line with treatment failures observed, and molecular markers of SP resistance should be closely monitored

Streptococcus agalactiae Serotype Distribution and Antimicrobial Susceptibility in Pregnant Women in Gabon, Central Africa

Neonatal invasive disease due to Streptococcus agalactiae is life threatening and preventive strategies suitable for resource limited settings are urgently needed. Protective coverage of vaccine candidates based on capsular epitopes will relate to local epidemiology of S. agalactiae serotypes and successful management of critical infections depends on timely therapy with effective antibiotics. This is the first report on serotype distribution and antimicrobial susceptibility of S. agalactiae in pregnant women from a Central African region. Serotypes V, III, and Ib accounted for 88/109 (81%) serotypes and all isolates were susceptible to penicillin and clindamycin while 13% showed intermediate susceptibility to erythromycin

Making clinical trials a public norm for health decisions in sub-Saharan Africa

A clinical trial is intrinsically a collaborative undertaking. The complex steps, including identifying the biological mechanisms, discovering products, preclinical studies, and the clinical development from phase 1 to 3 clinical trials allowing market authorisation of a product, are unlikely to be feasible for a single institution or a country alone. Collaboration is therefore necessary to establish and maintain the research and innovation that is a prerequisite to tackle health threats, irrespective of the socioeconomic status of the countries (1)