ACT: artemisinin-based combination therapy
CDC: Centers for Disease Control and Prevention
cytbc1: cytochrome bc1
G6PD: glucose-6-phosphate dehydrogenase
tmax: time to reach peak plasma drug concentration
WHO: World Health Organization
GLOBAL IMPACT OF MALARIA
Malaria remains among the top five causes of death among children younger than 5 years, affects about a quarter of a billion people, and caused over 600,000 deaths in 2021 (World Health Organization, 2021). Malaria transmission occurs in regions of Africa, Latin and South America, Asia, the Middle East, the South Pacific, and the Caribbean (Figure 66–1). This disease is caused by infection with protozoan parasites of the genus Plasmodium, five species of which are known to infect humans: P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi. P. falciparum and P. vivax cause most malarial infections worldwide. On the basis of genetic data, P. ovale has recently been subdivided in two subspecies, P. ovale wallikeri and P. ovale curtisi. P. falciparum accounts for the majority of the burden of malaria in sub-Saharan Africa and causes most severe disease and deaths. P. vivax accounts for half of the malaria burden in South and East Asia and more than 80% of the malarial infections in the Americas and has been underappreciated as a cause of severe malaria (Baird, 2013).
Malaria-endemic countries. A. Eastern Hemisphere. B. Western Hemisphere. A country is shaded orange even if malaria is endemic in just a portion of that country. Large regions not shown on the maps (e.g., Scandinavia, Russia, Canada, U.S., Tasmania, New Zealand) are nonendemic for malaria. In areas of endemic malaria, the disease is largely chloroquine resistant. For up-to-date information, consult the CDC’s Malaria Information and Prophylaxis, by Country (https://www.cdc.gov/malaria/travelers/country_table/a.html; accessed January 12, 2022). (Reproduced from Centers for Disease Control and Prevention, https://wwwnc.cdc.gov/travel/yellowbook/2020/travel-related-infectious-diseases/malaria; accessed January 12, 2022).
Over the past half-century, malaria parasites worldwide—primarily P. falciparum and P. vivax—have become increasingly resistant to antimalarial drugs, including chloroquine (Djimde et al., 2001; Fidock et al., 2000; Warhurst, 2001), mefloquine (White et al., 2014), quinine (White et al., 2014), sulfadoxine/pyrimethamine (Artimovich et al., 2015; Plowe et al., 1995; Sibley et al., 2001), and atovaquone (Garcia-Bustos et al., 2013; Kessl et al., 2007). In response, new, multipronged international public-private partnerships as well as other funding agencies and sources have emerged to create new pipelines that advance drug candidates from discovery to clinical development (Hemingway et al., 2016; Wells et al., 2010, 2015).
BIOLOGY OF MALARIAL INFECTION