Conclusions and outstanding

questions from recent APMEN G6PD meeting

LORENZ VON SEIDLEIN, SARAH AUBURN, EFFIE ESPINO, DENNIS SHANKS, QIN CHENG, JAMES MCCARTHY, KEVIN BAIRD, CATHERINE MOYES,

ROSALIND HOWES, DIDIER MENARD, GERMANA BANCONE, ARI WINASTI-SATYAHRAHA, LASSE S.

VESTERGAARD, JUSTIN GREEN, GONZALO DOMINGO, SHUNMAY YEUNG, RIC PRICE

Review of key knowledge gaps in G6PD deficiency with regard to the safe clinical deployment of 8-

aminoquinoline treatment regimens Incheon, Korea, May, 2012

1. INTRODUCTION 2. KEY RESEARCH PRIORITIES

Outline

Introduction

8-aminoquinolines (e.g. primaquine, tafenoquine) play a central role in malaria elimination Vivax hypnozoites: Relapse

Falciparum gametocytes: Interruption of transmission – SSA Containment of artemisinin resistance

Pv

Pf

Current control strategies are less effective against P. vivax than P.falciparum

Pf

Pv

Thailand: 1965-2001

Colombia: 1960-2008

Source: Oliveira-Ferreira et al Malaria J 2010, Sattabongkot et al Trends in Parasite 2004; Rodriguez et al Mem Inst Oswaldo Cruz, 2011

Brazil : 1960-2009

Primaquine

Successor of plasmoquine More than 60 years licensed Profound ignorance regarding the pharmaco-kinetics and

pharmaco-dynamics

The traditional drug development pathway has been established over the last 60 years:

Phases I →II → III → License →IV

The clinical development plan for primaquine does not exist

PQ

Phase IV Phase I Phase III Phase II

G6PD deficiency

An obscure, incompletely yet common congenital enzyme deficiency.

G6PD deficiency appears to be the single most significant risk factor for haemolysis after administration of 8-aminoquinolines G6PD deficiency is not the only risk factor Not all people with G6PD deficiency haemolyse after

the administration of primaquine.

Key Research Priorities

1)Exploration of less threatening but efficacious doses of primaquine or tafenoquine for the radical cure of vivax malaria and single dose therapy to reduce falciparum transmission and hence the containment of artemisinin resistance.

2) Determining the correlation between genotype, enzyme activity, cofactors and the severity of haemolysis

3) Understanding of the relationship between primaquine and tafenoquine dose and risk of haemolysis in G6PD normal and deficient individuals

4) Consensus on the level of haemolysis that constitutes unacceptable clinical risk to the patient

5) Investigation of the normal level of haemolysis in uncomplicated malaria without primaquine treatment, to allow the risk benefit of deploying or withholding primaquine regimens.

FACTORS CONTRIBUTING TO ANEMIA AFTER UNCOMPLICATED FALCIPARUM Price et al AJTMH 2001

6) What are the test characteristics (e.g. sensitivity and specificity) of rapid tests in various populations and field conditions? 1) Direct tests

• Spectrophotometry • ”Beutler’s” fluorescent spot test

2) Indirect tests • Methaemoglobin reduction test (MRT) • Brilliant cresyl blue, resazurin, or formazan ring tests

3) Cytochemical typing • Methaemoglobin elution test • Cytofluorometric assay

4) Rapid tests • Hirono – 1-methoxy PMS sephadex method • WST8/1-methoxy PMS method

5) Rapid, point of care tests • BinaxNow® G6PD test • CareStart® G6PD deficiency screening test

7) High resolution mapping of G6PD deficiency and haemolysis risks in malaria endemic regions

8) Analysis of cost-effectiveness of G6PD deficiency tests

What threshold are stakeholders, including regulatory agencies willing to accept for risk of haemolysis in malaria patients and healthy people events given a societal goal of elimination in patients and healthy individuals.

The End