How Much Primaquine to Kill Hypnozoites?

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1 Safe Primaquine Dosing in the Treatment of P vivax: : Role of G6PD Prof G. Dennis Shanks Australian Army Malaria Institute and Centre for Military and Veterans Health COL US Army (retired)

2 Treatment of Vivax Malaria Blood schizonticide (ACT or chloroquine) followed by 8- aminoquinoline to kill residual liver parasites Primaquine only current drug to kill hypnozoites How do we work around the risk of hemolytic risk due to G6PD deficiency?

3 How Much Primaquine to Kill Hypnozoites? Total dose of primaquine is what is important, not how fast / slow you give it Likely that the molecule that kills the hypnozoite is a metabolite of primaquine Always see a few persons who continue to relapse despite what one thinks should have been adequate primaquine ( >5 mg/kg)

4 Death from Pamaquine Hemolysis 1926 on the 4th day of treatment, after the fever had disappeared he developed profound anemia, leucocytosis, jaundice, nausea, vomiting, and somnolence. He died within 48 hrs of the onset of this sudden attack. The toxic influence of plasmochin compound was suspected to have played an important role in the cause of death

5 Tolerance of 8-Aminoquinolines 15 mg primaquine daily found to be tolerated in black US soldiers whereas 30 mg was not due to hemolysis Chlorproguanil Dapsone Artesunate (CDA) failed largely on basis of G6PD Tafenoquine hemolysis occurred in A- women when given 1200 mg over 3 days

6 Typical Hemolytic Episode with Primaquine Begins with malaise, weakness, and abdominal or lumbar pain progressing to fever, nausea, vomiting, fatigue After an interval of several hours to 2-3 days the patient develops jaundice and dark urine, due to haemoglobinuria Anemia is due largely to intravascular hemolysis with haemoglobinuria

7 Glucose 6 Phosphate Dehydrogenase Glucose 6 phosphate dehydrogenase (G6PD) key erythrocytic enzyme that is essential for life G6PD deficiency is one of world s most common genetic polymorphisms selected by malaria 100 s of variants found from evolutionary selection by falciparum malaria Howes RE, Piel FB, Patil AP et al. A map of G6PD deficiency prevalence and estimates of affected populations in malaria endemic countries. PLoS Med (submitted)

8 PLoS One Sep 30;4(9):e7246. March AQ Safety Issues Slide 8

9 SP + artesunate (AS) + a single dose of primaquine (PQ; 0.75 mg/kg of body weight) in children Antimicrob Agents Chemother May;54(5):1762-8

10 Most G6PD Persons Do Not Haemolyse Uncertain what combination of events leads to hemolytic event when given primaquine Drug and/or metabolite leading to oxidative stress in vulnerable erythrocyte Probably an exaggeration of normal means by which body identifies old erythrocytes for elimination

11 How To Test for G6PD? Phenotypic G6PD Testing = enzyme activity Qualitative spot screens Detects those with 30% activity Quantitative Testing Range of G6PD activity, measured at 30 C, is 7 to 10 IU/g normally Genotypic G6PD testing Identifies point mutations

12 Isabel, Solomon Islands Field Trial % deficient in WHO class I- II (<30% normal) Distribution of enzyme deficiency concentrated in males as expected in X linked traits Females unlikely to haemolyze unless homozygous deficient gene Kuwahata M,et al,malar J Aug 5;9:223.

13 What Is Acceptable Risk for Public Health? 1:1000 Thai soldiers haemolysed when given 45 mg primaquine single dose 1: million persons receiving oral polio vaccine become paralysed Mass drug administration in China and Nicaragua had reported hemolytic events in areas with very low G6PD

14 Trials to Determine Hemolytic Threshold Difficult to do especially with current IRB and ethical controls G6PD hemolysis is known to be variable both genetically and phenotypically On-going studies with tafenoquine in Thais with Mahidol variant G6PD

15 Questions for Discussion Is there a safe primaquine dose that does not require G6PD screening? If one decides to screen, can it be done accurately enough to prevent hemolysis? What studies are needed to help us decide what to do with primaquine?