**7. Targeting vivax malaria: a bottleneck to malaria elimination**

As opposed to *P. falciparum* infection, which does not have latency (dormant), *P. vivax* causes two distinct infection syndromes, one that actively proliferates and the other latent due to hypnozoites. Each of these *P. vivax* forms requires distinct therapeutic treatments and the latent form cannot be diagnosed [152]. Most acute attacks of *P. vivax* in endemic areas originate from hypnozoites, and unless that reservoir is aggressively attacked, elimination of transmission may be an unrealistic goal.

Treatment of latent vivax represents an important challenge as the only known therapies are 8-aminoquinoline drugs, which results in acute hemolytic anemia in patients deficient in glucose-6-phosphate dehydrogenase (G6PD)—a highly polymorphic inherited disorder affecting 1–30% of residents of malaria-endemic nations [153]. The single low dose of primaquine against gametocytes of *P. falciparum* does not threaten the G6PD deficient subjects [154]. Another challenge is that the parasitemia of vivax malaria patients is typically an order of magnitude lower than falciparum malaria, causing larger proportions of parasitemia to fall below diagnostics detection thresholds [152]. In addition, vivax malaria patients may exhibit very low parasitemia, and yet become severely ill. These fundamental distinctions between the two dominant human malarias explain why *P. vivax* is relatively unaffected by interventions tailored to control *P. falciparum* calling for new strategies needed for combatting vivax malaria [155].

In addition, *P. vivax* has the ability to develop at lower temperature than *P. falciparum* and has a shorter sporogonic cycle in the vector, which results in *P. vivax* extending beyond tropical climates into temperate regions. This ability, combined with its early-biting, outdoor-feeding and outdoorresting behavior of vector mosquito species, also makes them less susceptible to vector control measures such as IRS, which have proven effective against transmission of *P. falciparum* [156]. Also having dormant forms in the liver (hypnozoites) mean that one successful infection will generate a number of parasitological and clinical episodes without reinfection. Therefore, recurrent cases cannot be prevented via vector control, though, paradoxically, successful transmission control of vivax malaria could reduce the disease burden more than that of *P. falciparum*, because avoiding one infection will result in preventing a number of clinical episodes over several years [155].

predominant mosquito in the forest compared to farm and village, and was biting macaques at ground level and at six meters in the canopy compared to three meters. The biting ratio of monkey *versus* human for *An*. *latens* was 1:1.3 [121]. *An. introlatus* (Leucosphyrus Complex) [142] was biting in the early part of the night from 19:00 h to 21:00 h and was the predominant mosquito in Hulu Selangor where cases of *P. knowlesi* were reported. Most recently, *An. balabacensis* (Leucosphyrus Complex) has been incriminated as vector of *P. knowlesi* in Sabah [123], as well as human malaria and Bancroftian lymphatic filariasis due to *Wuchereria bancrofti* [143–145].

Although an increased number of countries are successfully eliminating human malaria in recent years, no country has yet eliminated non-human malaria, which adds another layer of complexity to be addressed. The complex situation of malaria is Southeast Asia is very unique from the rest of the tropical countries. More effort is needed to study the host switching mechanisms between the parasites in humans, macaques and vectors. A series of review papers have been published over the years and all these have indicated the importance of addressing the problem caused by *P. knowlesi,* if malaria elimination is to be successful in the region [113, 146–151].

As opposed to *P. falciparum* infection, which does not have latency (dormant), *P. vivax* causes two distinct infection syndromes, one that actively proliferates and the other latent due to hypnozoites. Each of these *P. vivax* forms requires distinct therapeutic treatments and the latent form cannot be diagnosed [152]. Most acute attacks of *P. vivax* in endemic areas originate from hypnozoites, and unless that reservoir is aggressively attacked, elimination of

Treatment of latent vivax represents an important challenge as the only known therapies are 8-aminoquinoline drugs, which results in acute hemolytic anemia in patients deficient in glucose-6-phosphate dehydrogenase (G6PD)—a highly polymorphic inherited disorder affecting 1–30% of residents of malaria-endemic nations [153]. The single low dose of primaquine against gametocytes of *P. falciparum* does not threaten the G6PD deficient subjects [154]. Another challenge is that the parasitemia of vivax malaria patients is typically an order of magnitude lower than falciparum malaria, causing larger proportions of parasitemia to fall below diagnostics detection thresholds [152]. In addition, vivax malaria patients may exhibit very low parasitemia, and yet become severely ill. These fundamental distinctions between the two dominant human malarias explain why *P. vivax* is relatively unaffected by interventions tailored to con-

trol *P. falciparum* calling for new strategies needed for combatting vivax malaria [155].

In addition, *P. vivax* has the ability to develop at lower temperature than *P. falciparum* and has a shorter sporogonic cycle in the vector, which results in *P. vivax* extending beyond tropical climates into temperate regions. This ability, combined with its early-biting, outdoor-feeding and outdoorresting behavior of vector mosquito species, also makes them less susceptible to vector control measures such as IRS, which have proven effective against transmission of *P. falciparum* [156]. Also having dormant forms in the liver (hypnozoites) mean that one successful infection will generate a number of parasitological and clinical episodes without reinfection. Therefore, recurrent cases cannot be prevented via vector control, though, paradoxically, successful transmission control of

**7. Targeting vivax malaria: a bottleneck to malaria elimination**

transmission may be an unrealistic goal.

108 Towards Malaria Elimination - A Leap Forward

Vivax malaria is diagnosed late, because infected people get ill with low parasite densities, which cannot be detected with current diagnostics, such as RDTs and microscopy. Delayed diagnosis means not only delayed treatment (hence prolonged morbidity, especially anemia) but also ability to transmit over an extended period. This is further amplified by the fact that mature gametocytes appear simultaneously with asexual forms—hence transmission occurs before diagnosis and treatment [157, 158].

As recently described [156], an effective *P. vivax* control and elimination toolbox should include:


In conclusion, the malaria community needs to address these challenges and create a viable strategy to achieve vivax elimination goals, providing novel solutions for overcoming critical bottlenecks. This process needs to begin now to enhance treatment practice for 8-aminoquinoline drugs based radical cure. Highlighting the benefits of radical cure for the patient and community will improve prescription practice and patient adherence [160]. Coupling this with improved access to adequate G6PD testing will pave the way for the introduction of tafenoquine, with huge potential to accelerate the elimination of *P. vivax*.
