Increased Gametocytemia after Treatment: An Early Parasitological Indicator of Emerging Sulfadoxine‐Pyrimethamine Resistance in Falciparum Malaria

Barnes, Karen I.; Little, Francesca; Mabuza, Aaron; Mngomezulu, Nicros; Govere, J.; Dürrheim, David N; Roper, Cally; Watkins, Bill; White, Nicholas J.

doi:10.1086/587645

Cited by 102 publications

(95 citation statements)

References 29 publications

(44 reference statements)

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“…People with resistant parasites tend to have enhanced gametocyte carriage and are more infectious to mosquitoes than individuals with wild parasites, even during the primary infection. 33,34 Although gametocyte carriage is substantially reduced after the addition of AS to SP, 35 gametocyte transmission to mosquitoes is not completely halted 36 and data are needed to determine whether this ACT alters the ratio of resistant to sensitive infections seen after SP monotherapy.…”

Section: Discussionmentioning

confidence: 99%

Five Years of Large-Scale dhfr and dhps Mutation Surveillance Following the Phased Implementation of Artesunate Plus Sulfadoxine-Pyrimethamine in Maputo Province, Southern Mozambique

Raman¹,

Little²,

Roper³

et al. 2010

The American Society of Tropical Medicine and Hygiene

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Abstract. Accumulation of mutations in dihydrofolate reductase ( dhfr ) and dihydropteroate synthetase ( dhps ) is strongly associated with sulfadoxine-pyrimethamine (SP) treatment failure. Routine surveillance for these resistance markers was conducted annually at 26 sentinel sites in Maputo Province, Mozambique, before and after the phased deployment of artesunate plus SP (AS-SP), with 15,758 children sampled between 2004 and 2008. Mean asexual parasite prevalence, polymerase chain reaction (PCR) corrected, decreased from 44.2% in 2004 to 3.8% in 2008 ( P < 0.0001). Among the 2,012 PCR-confirmed falciparum samples, the dhfr triple mutation remained close to fixation, whereas both dhps double and dhfr/dhps "quintuple" mutations increased from 11.0% in 2004, to 75.0% by 2008 ( P < 0.0001). Adding artesunate to SP did not retard the spread of SP-resistant parasites. The high "quintuple" mutation prevalence suggests a limited useful therapeutic lifespan of AS-SP for treating uncomplicated malaria, and may curb efficacy of SP-monotherapy for intermittent preventive treatment in Mozambique.

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Section: Discussionmentioning

confidence: 99%

Five Years of Large-Scale dhfr and dhps Mutation Surveillance Following the Phased Implementation of Artesunate Plus Sulfadoxine-Pyrimethamine in Maputo Province, Southern Mozambique

Raman¹,

Little²,

Roper³

et al. 2010

The American Society of Tropical Medicine and Hygiene

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“…Total parasite density in an individual can influence gametocytogenesis as a relatively higher concentration of gametocytes was observed in individuals with low-density infections when compared with those with high-density infections . Evidence from clinical observations during human or experimental infections suggests an increased gametocyte production following drug treatment (Buckling et al 1997;Price et al 1999;Bousema et al 2003;Sowunmi et al 2011), indicating that inefficient treatment and/or parasite recrudescence are associated with higher gametocyte numbers (Price et al 1999;Barnes et al 2008). These studies suggest that selection of drug-resistant parasite clones may be associated with increased chances of transmission; however, this hypothesis has yet to be systematically tested given the complex relationship between drug resistance and malaria transmission, which involves factors such as multiplicity of resistant clones, transmission intensity, and the genetic nature of resistance traits (Talisuna et al 2003).…”

Section: Mechanisms Of Sexual Commitment and Gametocyte Sequestrationmentioning

confidence: 99%

Biology of Malaria Transmission

Meibalan

Marti

2016

Cold Spring Harb Perspect Med

135

137

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Understanding transmission biology at an individual level is a key component of intervention strategies that target the spread of malaria parasites from human to mosquito. Gametocytes are specialized sexual stages of the malaria parasite life cycle developed during evolution to achieve crucial steps in transmission. As sexual differentiation and transmission are tightly linked, a deeper understanding of molecular and cellular events defining this relationship is essential to combat malaria. Recent advances in the field are gradually revealing mechanisms underlying sexual commitment, gametocyte sequestration, and dynamics of transmissible stages; however, key questions on fundamental gametocyte biology still remain. Moreover, species-specific variation between Plasmodium falciparum and Plasmodium vivax transmission dynamics pose another significant challenge for worldwide malaria elimination efforts. Here, we review the biology of transmission stages, highlighting numerous factors influencing development and dynamics of gametocytes within the host and determinants of human infectiousness. C urrent measures for malaria elimination have been inspired by the Global Malaria Eradication Program (GMEP), which operated under the World Health Organization (WHO) between 1955 and 1969. The strategy of GMEP was largely based on dichlorodiphenyltrichloroethane (DDT)-based indoor residual spraying (DDT-IRS) complemented with mass drug administration (Pampana 1969). Although GMEP was able to eliminate malaria from many regions of the world, it was eventually abandoned because of technical challenges, increasing spread of both insecticide resistance and drug-resistant parasite strains, and lack of continuous political support (Najera et al. 2011 ual parasites and early transmission stages, whereas mature infectious transmission stages are unaffected. To block transmission, ACT is often combined with the only transmissionblocking drug on the market, Primaquine. However, recent emergence of artemisinin resistance in Southeast Asia asks for urgent evaluation of alternative treatment strategies (Noedl et al. 2008;Dondorp et al. 2009;Mbengue et al. 2015;Straimer et al. 2015).Of the five Plasmodium species known to cause malaria in humans, Plasmodium falciparum is lethal and responsible for severe disease pathology and the majority of deaths due to malaria, especially in sub-Saharan Africa. Plasmodium vivax typically causes milder infections than P. falciparum but has a much greater geographical distribution (Gething et al. 2012). The clinical symptoms of malaria are largely a result of the replication of asexual stages in human blood, but transmission to mosquitoes is only achieved through the development of sexual stages, termed gametocytes. To abrogate transmission of P. falciparum, we must be able to clear asexual and sexual stages from the human host, eventually rendering an individual noninfectious to mosquitoes. However, in the case of P. vivax, elimination is highly challenging because of the relapse of dormant liver-stage h...

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“…Treatment with pyrimethamine/sulfadoxine often causes elevated gametocytosis (41,42). Increased gametocytogenesis may have contributed to increased malaria transmission and thereby is likely to be associated with rapid spread of pyrimethamine/sulfadoxine resistance in the endemic areas.…”

Section: -2 Pyrimethamine and Sulfadoxinementioning

confidence: 99%

Evolution of Plasmodium falciparum drug resistance: implications for the development and containment of artemisinin resistance

Mita¹,

Tanabe²

2012

Jpn J Infect Dis

100

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Increased Gametocytemia after Treatment: An Early Parasitological Indicator of Emerging Sulfadoxine‐Pyrimethamine Resistance in Falciparum Malaria

Cited by 102 publications

References 29 publications

Five Years of Large-Scale dhfr and dhps Mutation Surveillance Following the Phased Implementation of Artesunate Plus Sulfadoxine-Pyrimethamine in Maputo Province, Southern Mozambique

Five Years of Large-Scale dhfr and dhps Mutation Surveillance Following the Phased Implementation of Artesunate Plus Sulfadoxine-Pyrimethamine in Maputo Province, Southern Mozambique

Biology of Malaria Transmission

Evolution of Plasmodium falciparum drug resistance: implications for the development and containment of artemisinin resistance

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