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

Abstract

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.

Estimating the probable cause of recurrence in Plasmodium vivax malaria: relapse, reinfection or recrudescence?

“…There was little evidence of recrudescence for all treatments considered. These results are consistent with previous modelling results from the same area [33].…”

“…This pooled analysis confirms the high periodicity of relapse for the frequent relapse phenotype present in Southeast Asia [6]. Some previous statistical models of vivax relapse have assumed a constant rate of awaking hypnozoites [27,33-35]. Our pooled analysis takes into account post treatment prophylaxis and shows that the pattern of relapsing infections does not fit a simple constant rate model.…”

The Vivax Surveyor: Online mapping database for Plasmodium vivax clinical trials

“…In some equatorial regions relapse occurs early (within 21–42 days) and frequently (in over 70% of patients) (Adekunle et al., 2015, Robinson et al., 2015). Conversely, in temperate climates the risk of relapse is considerably lower and recurrent infections occur much later (White, 2011).…”

“…The majority of P. vivax recurrences is estimated to be secondary to relapses from the parasites’ dormant hypnozoite stages (Adekunle et al., 2015, Robinson et al., 2015). Hence, as countries progress towards elimination of all malaria species, there is an increasing imperative to achieve safe and effective radical cure to tackle both the blood and liver stages of the parasite.…”

Multi-omics Integrative Analysis of Acute and Relapsing Malaria in a Non-Human Primate Model ofP. vivaxinfection

“…These are known as hypnozoites and can persist and exit dormancy causing relapsing blood-stage infections weeks, months or years after an initial blood-stage infection has been cleared. Relapses are thought to be responsible for most blood-stage infections in P. vivax endemic areas (Adekunle et al, 2015), although there is difficulty in determining this. Regardless, it is widely accepted that relapsing P. vivax infection possesses the potential to continue transmission and cause repeated bouts of malaria.…”