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The human malaria parasite Plasmodium vivax imposes unique challenges to its control and elimination. Primary among those is the hypnozoite reservoir of infection in endemic communities. It is the dominant source of incident malaria and exceedingly difficult to attack due to both inability to diagnose latent carriers and the potentially life-threatening toxicity of primaquine in patients with an inborn deficiency of G6PD, the only therapeutic option against hypnozoites. Large segments of endemic populations are not eligible for primaquine, and alternative strategies for managing the threat of relapse in any group have not been optimized or validated. Association of risk of primaquine failure against latent P. vivax with impaired alleles of P450 2D6 exacerbates the substantial pool of primaquine ineligibles. Resistance to chloroquine against acute P. vivax malaria commonly occurs; alternative therapies like ACTs are effective but seldom evaluated as a partner drug to primaquine in the essential radical cure. Many of the Anopheles mosquito vector of P. vivax in South and Southeast Asia, where >90% of infections occur, thrive in a diversity of habitats and exhibit wide ranges of feeding and breeding behavior. This chapter explores many of these challenges and possible approaches in controlling and eliminating endemic vivax malaria.

Different malarial situations in Africa within the past 40 years are discussed in order to evaluate the impact of climatic and human factors on the disease. North of the equator, more droughts and lower rainfall have been recorded since 1972; and in eastern and southern Africa, there have been alternating dry and wet periods in relation to El Niño. Since 1955, the increase in human population from 125 to 450 million has resulted in both expansion of land cultivation and urbanization. In stable malaria areas of West and Central Africa and on the Madagascar coasts, the endemic situation has not changed since 1955. However, in unstable malaria areas such as the highlands and Sahel significant changes have occurred. In Madagascar, cessation of malaria control programs resulted in the deadly epidemic of 1987-88. The same situation was observed in Swaziland in 1984-85. In Uganda, malaria incidence has increased more than 30 times in the highlands (1,500-1,800 m), but its altitudinal limit has not overcome that of the beginning of the century. Cultivation of valley bottoms and extension of settlements are in large part responsible for this increase, along with abnormally heavy rainfall that favored the severe epidemic of 1994. A similar increase in malaria was observed in neighboring highlands of Rwanda and Burundi, and epidemics have been recorded in Ethiopia since 1958. In contrast, in the Sahel (Niayes region, Senegal), stricken by droughts since 1972, endemic malaria decreased drastically after the disappearance of the main vector, Anopheles funestus, due to the destruction of its larval sites by cultivation. Even during the very wet year of 1995. An funestus did not reinvade the region and malaria did not increase. The same situation was observed in the Sahelian zone of Niger. Therefore, the temperature increase of 0.5 degree C during the last 2 decades cannot be incriminated as a major cause for these malaria changes, which are mainly due to the combination of climatic, human, and operational factors.

In the field, the kdr mutation, involved in pyrethroid resistance, has been found widely distributed in the Savanna form of Anopheles gambiae s.s., but never in wild populations of the Mopti form or An. arabiensis, even in areas where both occur in sympatry with resistant Savanna populations. Under laboratory conditions, Mopti and Savanna forms were fully able to interbreed and the kdr mutation was transmissible from one form to the other. Both forms appeared to be exposed to pyrethroid selection pressure in the field. The absence of the kdr mutation in the Mopti form and the total lack of Mopti-Savanna heterozygotes in field populations provides further evidence of a pre-copulatory barrier to gene flow between these two forms. Molecular markers, including kdr, are powerful tools for studying population genetics and circulation of resistance genes, and should be used through an integrated approach for a better understanding of the speciation process.

Population genetic studies of vectors are essential for (i) the determination of their taxonomic status and consequently the definition of their vectorial role in the transmission of pathogenic agents; (ii) the evaluation of the species genetic variability and the estimation of their capacities of adaptation to selection pressure; (iii) an estimation of gene flow among populations in order to evaluate their degree of isolation and gene circulation, especially resistance genes. Among the malaria vectors taken as examples on three continents, Africa, South-East Asia and Latin America, the large majority of the species showed an important polymorphism. The Gambiae Complex, which is by far the most studied one, includes at present 7 species with the recent description of An. quadriannulatus A and B from Ethiopia. An. gambiae s.s. includes itself 5 chromosomal forms. One of them, the Mopti form, should be considered as a species unto itself. For An. arabiensis, a strong differentiation has been observed among the populations from Senegal and the Indian Ocean Islands. The kdr mutation, which confers resistance to pyrethroid knockdown effect, has never been found either in the Mopti form, or An. arabiensis, indicating a restricted gene flow between these latter two and An. gambiae s.s. The speciation process of the Gambiae Complex seems to be a recent phenomenon due to environmental selection pressure. Species of the Funestus Group are distinguishable by morphological characters. The genetic study of An. funestus s.s. did not show the presence of a complex, in spite of high polymorphism and population structure. Anophelines from eastern areas present an important biodiversity. The Minimus Complex includes two species, A and C, which are widely distributed in South-East Asia. Species A is strongly endophilic, on the contrary species C is at once more exophilic and zoophilic. The latter species might have been selected by DDT indoor house spraying. After numerous taxonomic investigations, the Dirus Complex includes now 7 species. In Latin America, An. pseudopunctipennis clustered into three geographic populations which are under a speciation process. One covers North America and Guatemala, the other South America and Belize, whilst the last one is restricted to Grenada Island. On the contrary, An. darlingi showed little morphologic and genetic variability throughout the species geographic range suggesting the existence of a single species. The main objective of these studies is to implement a more selective approach of vector control programs in relation to the incriminated species, their bioecology and their role in malaria transmission. The improvement of efficiency and selectivity of vector control is becoming a major goal in order to make the best out of the available tools and control the impact of interventions on the environment.

The behavioral responses of 4 populations of #Anopheles albimanus$ females to DDT, permethrin, and deltamethrin were characterized in excito-repellency tests. One test population (ST) from El Salvador has been maintained as a colony for 20 years. A second population (ES) from Guatemala was colonized in 1992. Third and fourth populations consisted of field-caught specimens from Toledo District (TO) of southern Belize in 1994 and Corozal District (CO) of northern Belize, respectively. Females of ES, TO and CO populations rapidly escaped from direct contact with treated surfaces for each of the 3 insecticides. Similarities in escape responses of insecticide-resistant (ES) versus insecticide-susceptible populations (TO, CO) suggest that there is no relationship between physiological and behavioral responses of #An. albimanus$ populations to DDT, permethrin, and deltamethrin. Females from all but the ST colony escaped in greater numbers from chambers without direct contact with treated surfaces than from control chambers (P

The human malaria parasite Plasmodium vivax imposes unique challenges to its control and elimination. Primary among those is the hypnozoite reservoir of infection in endemic communities. It is the dominant source of incident malaria and exceedingly difficult to attack due to both inability to diagnose latent carriers and the potentially life-threatening toxicity of primaquine in patients with an inborn deficiency of G6PD, the only therapeutic option against hypnozoites. Large segments of endemic populations are not eligible for primaquine, and alternative strategies for managing the threat of relapse in any group have not been optimized or validated. Association of risk of primaquine failure against latent P. vivax with impaired alleles of P450 2D6 exacerbates the substantial pool of primaquine ineligibles. Resistance to chloroquine against acute P. vivax malaria commonly occurs; alternative therapies like ACTs are effective but seldom evaluated as a partner drug to primaquine in the essential radical cure. Many of the Anopheles mosquito vector of P. vivax in South and Southeast Asia, where >90% of infections occur, thrive in a diversity of habitats and exhibit wide ranges of feeding and breeding behavior. This chapter explores many of these challenges and possible approaches in controlling and eliminating endemic vivax malaria.