**2.1 Detection of hypnozoites**

Historically, until to date, very few, if any, progress that has been achieved with regard to the biology of hypnozoites. Owing to its relatively "benign" clinical manifestation, the need for developing a more effective and less side effect radical cure have been hindered by our inability to detect the presence of hypnozoites in the liver cells. The occurrence of relapses in *P. vivax* after primaquine therapy would be assumed to be the most reliable indication of resistance. Nevertheless, recurrent parasite following primary attack may originate from failed therapy against asexual blood stages (recrudescence), biting infectious anopheline mosquitoes (reinfection), and reactivation of hypnozoites (relapse).

Since parasite arising from relapse may be genetically heterologous [11–13], distinguishing these events using molecular technologies is not yet possible, and this imposes limitations in estimating primaquine efficacy against relapse or resistance. Our inability to detect the presence of hypnozoite lead us to the assumption that every acute attack of *P. vivax* shall also harbour hypnozoites in the liver cell and this is supported by the fact that without prescription of antirelapse, almost all acute attack will experience relapse within a year [14, 15]. Recent studies have tried to identify any protein (s) that are released by hypnozoites during its dormancy and some progress have been achieved in this endeavour. Although the finding is still a proof-of-principle, the presence of human arginase-I and an uncharacterized *P. vivax* protein in plasma-derived exosomes deserves further exploration on the potential to identify biomarkers of hypnozoite infection [16].
