Modeling the Dynamics of Plasmodium vivax Infection and Hypnozoite Reactivation In Vivo.

The dynamics of Plasmodium vivax infection is characterized by reactivation of hypnozoites at varying time intervals. The relative contribution of new P. vivax infection and reactivation of dormant liver stage hypnozoites to initiation of blood stage infection is unclear. In this study, we investigate the contribution of new inoculations of P. vivax sporozoites to primary infection versus reactivation of hypnozoites by modeling the dynamics of P. vivax infection in Thailand in patients receiving treatment for either blood stage infection alone (chloroquine), or the blood and liver stages of infection (chloroquine + primaquine). In addition, we also analysed rates of infection in a study in Papua New Guinea (PNG) where patients were treated with either artesunate, or artesunate + primaquine. Our results show that up to 96% of the P. vivax infection is due to hypnozoite reactivation in individuals living in endemic areas in Thailand. Similar analysis revealed the around 70% of infections in the PNG cohort were due to hypnozoite reactivation. We show how the age of the cohort, primaquine drug failure, and seasonality may affect estimates of the ratio of primary P. vivax infection to hypnozoite reactivation. Modeling of P. vivax primary infection and hypnozoite reactivation provides important insights into infection dynamics, and suggests that 90–96% of blood stage infections arise from hypnozoite reactivation. Major differences in infection kinetics between Thailand and PNG suggest the likelihood of drug failure in PNG. Author Summary: Plasmodium vivax is one of two major parasite species causing human disease. This parasite can lie dormant in the liver as a hypnozoite, before later reactivating to cause blood-stage infection. Treatment to eliminate the dormant hypnozoite stage relies mostly on a single drug—primaquine. Understanding the rate of primary infection versus hypnozoite reactivation is important to understanding primaquine efficacy and drug resistance, as well as the development of new drugs targeting hypnozoites. Here we use mathematical modeling to analyse data from two clinical cohorts and show that up to 96% of infections may be caused by hypnozoite reactivation. We also use modeling to understand the impact of drug resistance, seasonal infection and subject age. [ABSTRACT FROM AUTHOR]