Moderate Effect of Artemisinin-Based Combination Therapy on Transmission of

Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
The Journal of Infectious Diseases (Impact Factor: 6). 05/2006; 193(8):1151-9. DOI: 10.1086/503051
Source: PubMed


Background. Artemisinin-based combination therapy (ACT) reduces microscopically confirmed gametocytemia and mosquito infection. However, molecular techniques have recently revealed high prevalences of submicroscopic gametocytemia. Our objective here was to determine the effect of sulfadoxine-pyrimethamine (SP) monotherapy and treatment with SP plus amodiaquine (AQ), SP plus artesunate (AS), and artemether-lumefantrine (AL; Coartem) on submicroscopic gametocytemia and infectiousness.Methods. Kenyan children (n=528) 6 months-10 years of age were randomized to 4 treatment arms. Gametocytemia was determined by both microscopy and Pfs25 RNA-based quantitative nucleic acid sequence-based amplification (Pfs25 QT-NASBA). Transmission was determined by membrane-feeding assays.Results. Gametocyte prevalence, as determined by Pfs25 QT-NASBA, was 89.4% (219/245) at enrollment and decreased after treatment with SP plus AS, SP plus AQ, and AL. Membrane-feeding assays for a group of randomly selected children revealed that the proportion of infectious children was as much as 4-fold higher than expected when based on microscopy. ACT did not significantly reduce the proportion of infectious children but did reduce the proportion of infected mosquitoes.Conclusions. Submicroscopic gametocytemia is common after treatment and contributes considerably to mosquito infection. Our findings should be interpreted in the context of transmission intensity, but the effect of ACT on malaria transmission appears to be moderate and restricted to the duration of gametocyte carriage and the proportion of mosquitoes that are infected by carriers.

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Available from: Teun Bousema, Oct 20, 2014
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    • "QT-NASBA revealed much higher gametocyte prevalence than microscopy which supports similar findings from other African studies where gametocyte prevalence in patients ranged from 9-25% by microscopy but 68-89% by QT-NASBA [36] [37] [38] [39]. Because even low gametocyte densities can result in mosquito infection, molecular methods are more informative than microscopy for determining post-treatment transmission potential although both assays fall short of making definitive statements on the transmission-blocking potential of antimalarial drugs that requires mosquito feeding assays [39]. "
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    ABSTRACT: Background: Methylene blue (MB) has been shown to be safe and effective against falciparum malaria in Africa and to have pronounced gametocytocidal properties. Methods: Three days of treatment with artesunate (AS)-amodiaquine (AQ) combined with MB was compared with AS-AQ treatment in a randomized controlled phase IIb study; the study included 221 children aged 6-59 months with uncomplicated falciparum malaria in Burkina Faso. The primary end point was gametocyte prevalence during follow-up, as determined by microscopy and real-time quantitative nucleic acid sequence-based amplification (QT-NASBA). Results: The gametocyte prevalence of Plasmodium falciparum at baseline was 3.6% (microscopy) and 97% (QT-NASBA). It was significantly lower in the AS-AQ-MB than in the AS-AQ group on day 7 of follow-up (microscopy, 1.2% vs 8.9% [P < .05]; QT-NASBA, 36.7% vs 63.3% [P < .001]). Hemoglobin values were significantly lower in the AS-AQ-MB group than in the AS-AQ group at days 2 and 7 of follow-up. Vomiting of the study medication occurred significantly more frequently in the AS-AQ-MB group. Conclusions: The combination of MB with an artemisinin-based combination therapy has been confirmed to be effective against the gametocytes of P. falciparum. MB-based combinations need to be compared with primaquine-based combinations, preferably using MB in an improved pediatric formulation. Clinical Trials Registration: NCT01407887.
    The Journal of Infectious Diseases 09/2014; 211(5). DOI:10.1093/infdis/jiu540 · 6.00 Impact Factor
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    • "One further challenge, which is currently only partially answered, is the viability and infectivity of gametocytes following treatment. The majority of the studies analysed, with the exception of three studies in two settings (western Kenya and the Gambia) [26,46,59,61,66], did not have a study component (i e. feeding assays) that evaluated the viability and infectivity of the gametocytes that appear post treatment. Nevertheless, the limited available data suggest that ACT, and AL treatment in particular, are able to reduce the infectiousness of blood samples to mosquitoes when compared with non-ACT regimens [26,66]. "
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    ABSTRACT: While significant advances have been made in the prevention and treatment of malaria in recent years, these successes continue to fall short of the World Health Organization (WHO) goals for malaria control and elimination. For elimination strategies to be effective, limited disease transmission, achieved through rapid reduction in the infectious parasite reservoir and decreased gametocyte carriage, will be critical. Artemisinin-based combination therapy (ACT) forms the cornerstone of WHO-recommended treatment for uncomplicated Plasmodium falciparum malaria, and in combination with other effective interventions will undoubtedly play a vital role in elimination programmes. The gametocytocidal properties of artemisinins are a bonus attribute; there is epidemiological evidence of reductions in malaria incidence and transmission in African regions since the introduction of these agents. Many studies and analyses have specifically investigated the effects of the ACT, artemether-lumefantrine (AL) on gametocyte carriage. In this systematic review of 62 articles published between 1998 and January 2014, the effects of AL on gametocyte carriage and malaria transmission are compared with other artemisinin-based anti-malarials and non-ACT. The impact of AL treatment of asymptomatic carriers on population gametocyte carriage, and the potential future role of AL in malaria elimination initiatives are also considered. Despite the inherent difficulties in comparing data from a range of different studies that also utilized different diagnostic approaches to assess baseline gametocyte counts, the gametocytocidal effect of AL was proportionately consistent across the studies reviewed, suggesting that AL will continue to play a vital role in the treatment of malaria and contribute to clearing the path towards malaria elimination. However, the specific place of AL is the subject of much ongoing research and will undoubtedly be dependent on different demographic and geographical scenarios. Utilizing ACT, such as AL, within malaria elimination strategies is also associated with a number of other challenges, such as balancing potential increased use of ACT (e g, treatment of asymptomatic carriers and home-based treatment) with rational use and avoidance of drug resistance development.
    Malaria Journal 07/2014; 13(1):291. DOI:10.1186/1475-2875-13-291 · 3.11 Impact Factor
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    • "Second, there is lack of parasite molecular data that would have complemented the findings of this study. This is in light of the knowledge that sub-microscopic gametocytaemia plays a key role in malaria transmission, and that 3–10 fold increase in gametocyte carriage as determined by microscopy is seen when molecular detection methods are used [4,6-8,46]. Lastly, the original study was designed to address a different research question, and this may affect the statistical power of this study. "
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    ABSTRACT: Background The effects that artemether-lumefantrine (AL) has on gametocyte dynamics in the short-term have recently been described. However there is limited long-term longitudinal data on the effect of AL on gametocyte dynamics in asymptomatic children. Methods An epidemiological study was conducted in Kombewa, Western Kenya, in which 270 asymptomatic children aged between 12 and 47 months were enrolled. The subjects were randomized to receive either a course of AL or placebo at enrolment. Active follow-up was conducted for one year. Results The gametocyte prevalence and density dynamics throughout the study period mirrored that of the asexual forms. The proportion of initially parasitaemic subjects becoming gametocytaemic was significantly lower in the AL arm for the first 12 weeks following randomization. The geometric mean gametocyte density was lower in the AL arm for 2 weeks following randomization. None of the variables of interest had a statistically significant effect on the duration of gametocytaemia. There is no effect seen in subjects who are not parasitaemic at the time of drug administration. Conclusions The treatment of asymptomatic parasitaemic subjects with AL results in a significant reduction in the proportion of subjects who become gametocytaemic for at least 12 weeks.
    Malaria Journal 07/2014; 13(1):265. DOI:10.1186/1475-2875-13-265 · 3.11 Impact Factor
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