A randomized trial to monitor the efficacy and effectiveness by QT-NASBA of artemether-lumefantrine versus dihydroartemisinin-piperaquine for treatment and transmission control of uncomplicated Plasmodium falciparum malaria in western Kenya

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Abstract

Background

Many countries have implemented artemisinin-based combination therapy (ACT) for the first-line treatment of malaria. Although many studies have been performed on efficacy and tolerability of the combination arthemeter-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP), less is known of the effect of these drugs on gametocyte development, which is an important issue in malaria control.

Methods and results

In this two-arm randomized controlled trial, 146 children were treated with either AL or DP. Both groups received directly observed therapy and were followed for 28 days after treatment. Blood samples were analysed with microscopy and NASBA. In comparison with microscopy NASBA detected much more gametocyte positive individuals. Moreover, NASBA showed a significant difference in gametocyte clearance in favour of AL compared to DP. The decline of parasitaemia was slower and persistence or development of gametocytes was significantly higher and longer at day 3, 7 and 14 in the DP group but after 28 days no difference could be observed between both treatment arms.

Conclusion

Although practical considerations could favour the use of one drug over another, the effect on gametocytogenesis should also be taken into account and studied further using molecular tools like NASBA. This also applies when a new drug is introduced.

Trial registration

Current controlled trials ISRCTN36463274

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Most cited references 25

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Submicroscopic Plasmodium falciparum gametocyte densities frequently result in mosquito infection.

Petra Schneider, J Teun Bousema, Louis C. Gouagna … (2007)

Submicroscopic Plasmodium falciparum gametocytemia (<5,000 gametocytes/mL) is common and may result in mosquito infection. We assessed the relation between gametocyte density and mosquito infection under experimental and field conditions using real-time quantitative nucleic acid sequence-based amplification (QT-NASBA) for gametocyte quantification. Serial dilutions of NF54 P. falciparum gametocytes showed a positive association between gametocyte density and the proportion of infected mosquitoes (beta=6.1; 95% confidence interval [CI], 2.7-9.6; P=0.001). Successful infection became unlikely below an estimated density of 250-300 gametocytes/mL. In the field, blood samples of 100 naturally infected children showed a positive association between gametocyte density and oocyst counts in mosquitoes (beta=0.38; 95% CI, 0.14-0.61; P=0.002). The relative contribution to malaria transmission was similar for carriers with submicroscopic and microscopic gametocytemia. Our results show that transmission occurs efficiently at submicroscopic gametocyte densities and that carriers harboring submicroscopic gametocytemia constitute a considerable proportion of the human infectious reservoir.

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Effects of artemisinin derivatives on malaria transmissibility.

C Luxemburger, Ashleigh R. Price, L Paiphun … (1996)

On the western border of Thailand the efficacy of mefloquine in the treatment of falciparum malaria has declined while gametocyte carriage rates have increased, which suggests increased transmissibility of these resistant infections. We compared the following antimalarial drugs in relation to subsequent Plasmodium falciparum gametocyte carriage: mefloquine, halofantrine, quinine, and the artemisinin derivatives. Between 1990 and 1995 we assessed gametocytaemia in a series of prospective studies of antimalarial drug treatment in 5193 adults and children with acute uncomplicated falciparum malaria in an area of malarious hill forest on the western border of Thailand. Weekly parasite counts from thick and thin blood films were done during the 4-week (1990-93) or 9-week (1993-95) follow-up period. Gametocyte positivity rates and person gametocyte week (PGW) rates were calculated to measure gametocyte carriage and transmission potential. In primary P falciparum infections the gametocyte carriage rate was significantly higher after treatment with mefloquine than after treatment with the artemisinin derivatives (PGW 34.1 [95% CI 25.2-42.9] vs 3.9 [1.9-5.9] per 1000 person weeks; relative risk 8.0 [4.1-15.6]; p<0.0001). Recrudescent infections were associated with increased gametocyte carrier rates (relative risk 2.2 [1.6-3.0]; p<0.0001), but retreatment with artemisinin derivatives reduced subsequent gametocyte carriage 18.5 fold [3.5-98] compared with mefloquine retreatment and 6.8 fold (3.1-15.1) compared with quinine retreatment (p<0.001). The introduction of the artemisinin derivatives in routine treatment at this study site in mid 1994 was associated with a reduction in the subsequent incidence of falciparum malaria of 47 (25-69)% Although environmental changes affect vector numbers, and hence malaria incidence, artemisinin derivatives were found to reduce the transmission potential of falciparum malaria. Widespread introduction of artemisinin derivatives in the treatment of falciparum malaria may prevent the spread of multidrug resistance.

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Moderate effect of artemisinin-based combination therapy on transmission of Plasmodium falciparum.

Rein Houben, Laura J. Sutherland, Alma Tostmann … (2006)

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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Author and article information

Journal

Journal ID (nlm-ta): Malar J

Title: Malaria Journal

Publisher: BioMed Central

ISSN (Electronic): 1475-2875

Publication date Collection: 2008

Publication date (Electronic): 18 November 2008

Volume: 7

Page: 237

Affiliations

[1 ]Koninklijk Instituut voor de Tropen (KIT)/Royal Tropical Institute, KIT Biomedical Research, Meibergdreef 39, 1105 AZ Amsterdam, the Netherlands

[2 ]Centre for Infection and Immunity Amsterdam, (CINEMA), Division of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Centre, Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands

[3 ]International Centre for Insect physiology and Ecology (ICIPE), Mbita, Kenya

[4 ]Kenya Medical Research Institute (KEMRI), Centre for Biotechnology Research and Development, Nairobi, Kenya

Article

Publisher ID: 1475-2875-7-237

DOI: 10.1186/1475-2875-7-237

PMC ID: 2600646

PubMed ID: 19017387

SO-VID: 51d69e88-e94e-4637-8dec-256102a5ee2b

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

A randomized trial to monitor the efficacy and effectiveness by QT-NASBA of artemether-lumefantrine versus dihydroartemisinin-piperaquine for treatment and transmission control of uncomplicated Plasmodium falciparum malaria in western Kenya

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Abstract

Background

Methods and results

Conclusion

Trial registration

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Future Science Group: Coronavirus

Most cited references 25

Submicroscopic Plasmodium falciparum gametocyte densities frequently result in mosquito infection.

Effects of artemisinin derivatives on malaria transmissibility.

Moderate effect of artemisinin-based combination therapy on transmission of Plasmodium falciparum.

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