What happened earlier. APMEN-PATH CONSULTATION Manila, 10 / 11 February 2015

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1 What happened earlier APMEN-PATH CONSULTATION Manila, 10 / 11 February 2015

2 Background G6PD is essential enzyme of PPP G6PD gene is located on the X- chromosome: Homozygous, hemizygous individuals Heterozygous females G6PD activity profile is determined by: the half life and age of the red blood cells the half life of the G6PD enzyme => A short half life of the enzyme is associated to severity G6PDd is classified into classes I V Ideally based on adjusted male median

3 Why G6PD testing for radical cure? High numbers of permanent, asymptomatic Pv cases Reservoir for parasite Pv is chronic disease if untreated Risk of death from Pv infection comparable to Pf 8-Aminoquinolones are the only option for radical cure 8-Aminoquinolones induce haemolysis in G6PDd individuals => pre-treatment G6PDd testing

4 Some problems with testing Heterozygous females Universal quantitative cut off activity Specific per drug Specific per genotype? Dependent on Hb level at treatment start No test available so far is perfect, however testing with current assays available superior to no testing

5 Primaquine G6PD Dilemma Treating against relapse invites risk of death by drug, and not treating with primaquine invites risk of death by parasite.

6 What did the WHO say? PQ used since 1952 Based on US Army guidelines WHO recommends PQ treatment without testing (1960) US guidelines based on A- variant In 1981 WHO considers PQ safe but radical cure not sensible in endemic areas In 2010 WHO limits safe use of PQ to G6PD normal and A- variants In 2015 Pv is recognized as serious public health threat by WHO

7 Evidence Review Group 2014 The ERG considers recommending mandatory G6PD testing before radical cure WHO may make strong recommendations regarding the necessity of therapy against relapse in vivax malaria, and the necessity for testing for G6PD deficiency before doing so.

8 Diagnostic tests for G6PD deficiency Absorbance (340 nm) Quantitative test Fluorescence (blue) Fluorescent spot test Dye reduction Rapid tests Electro-chemistry Biosensors Cytochemical staining Microscopy and flow cytometry A. Normal B. Intermediate C. Deficient

9 Two leading product concepts Lateral flow - Qualitative similar to malaria RDT qualitative no instrument Electrochemistry - Quantitative similar to glucose meter quantitative requires an instrument

10 Why is a quantitative G6PD test useful? 1. Heterozygous females have a broad range of G6PD activities ranging from normal to deficient 2. Inherent inability of qualitative tests to discriminate intermediate G6PD activity.

11 Pharmacovigilance for radical cure Need to develop standardized protocols and tools Data sharing facilitated via WWARN platform UCSF has developed tool to assess AE in PQ treated individuals => PROMPT Currently implemented at 4 sites (Africa and Asia)

12 Field evaluation of G6PD RDT Conclusion: The CareStart G6PD RDT reliably detected moderate and severe G6PD deficient individuals (enzyme activity,30%), this novel point-of-care is a promising tool for tailoring appropriate primaquine treatment for malaria elimination

13 Feasibility study In 3 provinces in Cambodia Objectives To evaluate the validity of VMWs and HCS to determine G6PD status after the performance of the G6PD RDT To evaluate the feasibility of use of G6PD RDT on confirmed malaria patients by VMWs and HCS To evaluate the acceptability to VMWs, HCS and population tested as part of standard practices for malaria diagnosis and treatment. Study period 3 months

14 Country reports (see handout) Malaysia (M), Philippines (P), Cambodia (C ), Bangladesh (B) report decline of malaria over the last decade. PQ is included in all national treatment guidelines Malaria elimination targeted within next 10 years G6PD testing: M+C: mandatory (FST) P: recommended (FST) B: patient advised to watch for signs of haemolysis

15 Discussion group RDT RDT has better operational characteristics over Biosensor Control and test line desirable G6PD RDT and consumables should be clearly distinct from Malaria RDT Small packaging units desirable Cut off activity higher than FST RDT best suited for community and PHC setting, Biosensor better for referral centres Cost benefit analysis desirable for decision making

16 Discussion group Biosensor Readout not suitable for healthworker Hb measurement should be included Temp. correction should be included Sample collection directly on chip better than current system with capillary tube Ideally a direct treatment recommendation based on entered and measured variables would be provided

17 Discussion group Biosensor & RDT RDT best suited for community and PHC setting, Biosensor better for referral centres Possible algorithm: RDT G6PDd no / 8 week PQ G6PDn All males = PQ All females = Biosensor

18 Objectives Discussion today What evidence needs to be generated to make an informed decission on implementing routine testing before radical cure? What needs to happen in individual countries before implementation?

19 Thanks and enjoy the discussions!

Testing for G6PD deficiency for safe use of primaquine in radical cure of P. vivax and P. ovale

Testing for G6PD deficiency for safe use of primaquine in radical cure of P. vivax and P. ovale Webinar presentation to support the dissemination of the policy brief Silvia Schwarte, WHO/GMP e-mail: schwartes@who.int