Genetic Analysis of Primaquine Tolerance in a Patient with Relapsing Vivax Malaria

The Case

Conclusions

Acknowledgments

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Technical Appendix [99 KB - 5 pages]

Suggested Citation

A. Taylor Bright¹, Thamer Alenazi¹, Sandra Shokoples, Joel Tarning, Giacomo M. Paganotti, Nicholas J. White, Stanley Houston, Elizabeth A. Winzeler, and Stephanie K. Yanow

Author affiliations: University of California, San Diego, La Jolla, CA, USA (A.T. Bright, E.A. Winzeler); University of Alberta Hospital, Edmonton, Canada (T. Alenazi, S. Houston); King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia (T. Alenazi, S. Houston); Provincial Laboratory for Public Health, Edmonton, Canada (S. Shokoples, S.K. Yanow); Mahidol University, Bangkok, Thailand; University of Oxford, Oxford, UK (J. Tarning, N.J. White); “La Sapienza” University, Rome, Italy (G.M. Paganotti); University of Alberta, Edmonton, Canada (S.K. Yanow)

Abstract

Patients with Plasmodium vivax malaria are treated with primaquine to prevent relapse infections. We report primaquine failure in a patient with 3 relapses without any possibility of re-infection. Using whole genome sequencing of the relapsing parasite isolates, we identified single nucleotide variants as candidate molecular markers of resistance.

Of the 5 species of Plasmodium that cause human malaria, P. vivax has the broadest geographic distribution with 2.85 billion persons at risk throughout the world (1). Scientists are becoming increasingly aware of the potential severity of P. vivax infections and their effects on public health (2). A major challenge is the treatment of the dormant stages, hypnozoites, in the liver. Activation of hypnozoites from this reservoir causes subsequent blood-stage infections, or relapses, weeks to years after the primary infection.
Primaquine (PQ) remains the only approved agent to eliminate hypnozoites. Treatment failure, defined by the occurrence of relapses despite PQ therapy, is often ascribed to inadequate dosing, poor adherence, or reinfection (3). However, several cases of PQ tolerance without these confounding factors are reported (4,5). The mechanism underlying PQ tolerance is not understood, although host and parasite genetic factors are implicated. We describe the genetic analysis of parasite and host markers in a patient with 3 P. vivax malaria relapses in a malaria-nonendemic setting where reinfection was not possible.