Resuming the fight against relapse of Plasmodium vivax

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Frederick McBride
6 years ago
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1 Resuming the fight against relapse of Plasmodium vivax Professor J. Kevin Baird Head of Unit, Eijkman-Oxford Clinical Research Unit, Jakarta, Indonesia & Centre for Tropical Medicine Nuffield Department of Medicine University of Oxford, United Kingdom

2 A global problem

3 An Asia-Pacific problem P. falciparum P. vivax

4 An Asia-Pacific problem 91% of the global population at risk of P. vivax resides in Asia-Pacific

5 A pernicious problem Vivax malaria is often pernicious and life-threatening, NOT benign

6 A biologically complex problem Wellems & Miller NEJM 2005 Primary attack Relapses

7 An epidemiologically important problem

8 The trouble with primaquine Licensed in 1952 in combination with chloroquine for radical cure of P. vivax Hemolytic toxicity in patients with glucose-6- phosphate dehydrogenase deficiency Doses distributed over 14 days to mitigate risk without screening for G6PD deficiency

10 The calculus of hypnozoitocidal efficacy No therapy, reinfection Blood schizontocidal therapy, resistance to it, reinfection Blood schizontocidal & hynozoitocidal therapy, reinfection Sources of parasites in peripheral blood Relapse Recrudescence Reinfection Liver Blood Mosquito

11 The calculus of hypnozoitocidal efficacy Blood schizontocidal & hypnozoitocidal therapy, NO reinfection Blood schizontocidal & hypnozoitocidal therapy, NO reinfection No reinfection provides opportunity for unambiguous estimate of efficacy against relapse Sources of parasites in peripheral blood Relapse Recrudescence Reinfection Liver Blood Mosquito

12 A uniquely useful study population Indonesian troops routinely deployed to remote areas Movement in battalions of approx. 600 people for 6 months duty Often from densely populated & low malaria risk Java Often deployed to malaria high risk zones

13 Citation: Elyazar IR, Gething PW, Patil AP, Rogayah H, Sariwati E, Palupi NW, Tarmizi SN, Kusriastuti R, Baird JK, Hay SI: Plasmodium vivax malaria endemicity in Indonesia in PLoS ONE 2012, 7(5):e37325.

14 First study

Second study 2013-2014 Estimate the therapeutic safety and efficacy of primaquine against

15 Second study Estimate the therapeutic safety and efficacy of primaquine against relapse when combined with artesunate, artesunate-pyronaridine or with dihydroartemisinin-piperaquine

Study Design Randomized and open-label Artesunate alone + primaquine (30mg daily X 14d) Artesunate-pyronaridine + primaquine (30mg daily X 14d) Dihydroartemisinin-piperaquine + primaquine (30mg

16 Study Design Randomized and open-label Artesunate alone + primaquine (30mg daily X 14d) Artesunate-pyronaridine + primaquine (30mg daily X 14d) Dihydroartemisinin-piperaquine + primaquine (30mg daily X 14d) G6PD-normal soldiers returned from Papua having microscopically confirmed vivax malaria Directly observed therapy Active follow up to first recurrence of vivax malaria or 12 months

Screening Soldiers return to Java from Papua en masse by ship in February 28, 2013 Routine military health screening at port Arrival at permanent base at Sragen,

17 Screening Soldiers return to Java from Papua en masse by ship in February 28, 2013 Routine military health screening at port Arrival at permanent base at Sragen, Central Java within 48 hours Mass blood surveys commence in the first three weeks Passive & active surveillance until 1 July 2013, when study fully enrolled (n=180)

18 1096 Screened 232 Malaria 214 Eligible 180 Randomized 864 Negative Malaria 18 P. falciparum 26 Refused to participate 3 Over weight 2 Abnormal laboratory results 1 Had malaria drug 1 Under renal treatment 1 QTc prolonged 60 AS + PQ 60 AS-PYR + PQ 60 DHA-PP + PQ 2 withdraw 10 relapses 1 withdraw 9 relapses 7 relapses 48 12mo follow-up 50 12mo follow-up 53 12mo follow-up

19 Relapses Withdraw Relapses AS Alone + PQ

20 Relapses Withdraw Relapses AS-PYR + PQ

21 Relapses Relapses DHA-PP + PQ

22 Relapse Risk

23 Efficacy Against Relapse AS alone + PQ AS-PYR + PQ DHA-PP + PQ Control* Number of subjects Number of withdrawals Number of relapses Person-year at risk Incidence density: (events/person-year) Efficacy against relapse (%) % confidence interval % % % - 12-mo cumulative incidence: Efficacy against relapse (%) % confidence interval % % % - * Subjects received AS alone in the previous PQ trial

24 Third study: Battalion returns from 6mo deployment to Papua, Indonesia approximately January 2016 Positive for P. vivax all treated with DHA-PP and randomized to: Tafenoquine single dose + placebo primaquine daily for 14 days Placebo tafenoquine single dose + Primaquine 14 daily doses Placebo tafenoquine single dose + placebo primaquine daily for 14 days Randomized, double-blind, double-dummy, placebo-controlled

25 Supporters Partner institutions Armed Forces of Indonesia Faculty of Medicine University of Indonesia Funding & administration partners

Interpretation of the World Malaria Report Country Profile

Interpretation of the World Malaria Report Country Profile Acknowledgements This presentation was developed to help explain the components of the World Malaria Report Country Profile. The 2017 World Malaria