Oral Presentation First Malaria World Congress 2018

Improving malaria elimination strategies with pharmacogenomics: tackling the unique problems posed by Plasmodium vivax (#209)

Sarah C Charnaud 1 , Yi Wan Quah 1 , Ivo Mueller 1 2 3
  1. Population Health and Immunity, Walter and Eliza Hall Institute, Parkville, VIC, Australia
  2. Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
  3. Department of Parasites and Insect Vectors, Institut Pasteur, Paris, France

The Asia-Pacific region is aiming for malaria elimination by 2030, but despite falling malaria cases Plasmodium vivax persists and is the primary source of infection in many regions. The reasons for the greater persistence of P. vivax relate to its unique biology, most importantly its ability to relapse from long-lasting, dormant liver stages (hypnozoites).

There are no diagnostic tests for hypnozoites and the only currently available drug to clear hypnozoites is primaquine, which can cause severe haemolysis in people with glucose 6-phosphate dehydrogenase (G6PD) deficiency, and may not work in people with low cytochrome P450 2D6 activitiy1,2. Biochemical assays of G6PD activity levels do not accurately reflect the likelihood of a person haemolysing, particularly heterozygote women due to lyonisation. CYP2D6 metabolises primaquine and tafenoquine into their active form, and is involved in some part in the metabolism of 20-25% of all drugs in clinical use, making it extremely interesting to determine what drugs are likely to work or be contra-indicated in a population. The G6PD and CYP2D6 genes are large and diverse, with hundreds of variants and complex structural rearrangements, leading to a wide range of enzymatic activity.

The advent of novel long-read sequencing now makes it possible to sequence complex genes with multiple mutations. We have developed long amplicon barcoded sequencing protocols on the PacBio Sequel of 10 kb lengths of G6PD and CYP2D6. We link the genotypes with phenotypes of G6PD deficiency and CYP2D6 activity in populations in PNG and Solomon Islands. We find population level rates of mutations which can be used to optimise treatment. This protocol can be easily expanded to other genes and populations. This will allow rapid assessment of pharmocogenomic characteristics of malaria endemic populations and that information can be used to tailor antihypnozoite therapy to achieve optimal safety and efficacy in each community.

  1. Chu, C. S. et al. Haemolysis in G6PD Heterozygous Females Treated with Primaquine for Plasmodium vivax Malaria: A Nested Cohort in a Trial of Radical Curative Regimens. PLoS Med. 14, e1002224 (2017).
  2. Silvino, A. C. R. et al. Variation in Human Cytochrome P-450 Drug-Metabolism Genes: A Gateway to the Understanding of Plasmodium vivax Relapses. PLoS ONE 11, e0160172 (2016).