Plasmodium falciparum Gametocyte Carriage and Viability following Standard Monotherapy and Artesunate Combination Therapy for Uncomplicated Malaria

Plasmodium falciparum gametocytes are the biological agents necessary for malaria transmission between vertebrate hosts and mosquito vectors.  Gametocyte density is strongly correlated with transmission success (Drakeley et. al., 1999). Drug resistance spreads when gametocytes derived from resistant parasites are transmitted to and by Anopheles mosquito vectors.  The rate at which drug resistance spreads is influenced by the relative reproductive rates of drug sensitive versus drug resistant parasites, the ability of gametocytes to infect mosquitoes, intensity of transmission, levels of immunity in the human population and patterns of antimalarial use.
		Drug resistance spreads when gametocytes derived from resistant parasites are transmitted to and by Anopheles mosquito vectors.  The objectives of this study are:   To determine the association between the type of antimalarial drug administered and the level of P. falciparum gametocytemia prevalence and density (at all study sites).  To determine infectivity of gametocytes persisting in the host following administration of an effective schizontocidal (in Mpumalanga).

 

 In areas of relatively low and unstable malaria transmission, the rate is accelerated by lack of immunity which may otherwise serve to remove drug resistant parasites or gametocytes with resulting reduction in transmission (Peel et al., 1993; Lensen et. al., 1998; Hogh et. al., 1998; McKenzie & Bossert, 1998). Patients resident in these areas are symptomatic and seek treatment, bringing infections under selective drug pressure, while multiple infections are rare resulting in limited opportunity for loss of resistance through recombination breakdown due to outbreeding (Watkins & Msobo, 1993; Hill et. al., 1995; Hastings, 1997).  Outbreeding slows the spread of resistance (Dye et. al., 1997). 

Mature gametocytes of P. falciparum are insensitive to many schizontocidal drugs, including chloroquine (CQ) and sulphadoxine-pyrimethamine (SP) (Smalley and Sinden, 1997; Sinden 1983) with resultant survival of mature gametocytes of drug-sensitive parasites until the end of their natural life span (14 - 28 days) despite treatment.  Further decline in antimalarial drug efficacy results in a rise in the proportion of resistant infections, increased gametocyte carriage and greater transmission of resistant strains of P. falciparum with accelerated decline in drug sensitivity.  On the other hand effective drugs with rapid action on asexual stages of the parasites limit gametocytogenisis (Price et. al., 1996).  Chloroquine induces increased gametocytemia in chloroquine resistant lines (Handunnetti et. al., 1996; Roberts et. al., 1996) while SP induces increased gametocytemia in both SP-sensitive and SP resistant-lines (Hogh et al., 1995; Puta & Manyando, 1997; Hogh et.al. 1998; Govere et. al., 1999). 

Gametocytemia can be reduced by early treatment with an effective drug or by use of gametocytocidal agents (Sinden et. al., 1996).  The artemisinin derivatives dramatically reduce gametocyte carriage through their rapid effect on asexual parasites (Price et. al., 1996, 1997).  Furthermore artemisinin derivatives in combination with other antimalarial drugs delay drug resistance (White 1998), ensure high malaria cure rates (White et al., 1999) and reduce gametocyte carriage (Price et. al., 1997, 1999) during the treatment of malaria. 

In the proposed study, gametocytes will be harvested from patients recruited for the multi-centre in vivo malaria monotherapy resistance studies and subsequent study of the in vivo effectiveness of Artesunate plus SP combination for the treatment of uncomplicated falciparum malaria in southern Africa.

OBJECTIVES

 To determine the association between the type of antimalarial drug administered and the level of P. falciparum gametocytemia prevalence and density (at all study sites).

 To determine infectivity of gametocytes persisting in the host following administration of an effective schizontocidal (in Mpumalanga).

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