Malaria Diagnostics: Introduction to operational issues

Mark Perkins, MDChief Scientific Officer

Foundation for Innovative New Diagnostics

Conventional microscopy for malaria detection

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RDT use

ACT use

Scale up of RDTs and ACTs in India M

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Impact of RDT training interventionon antimalarial prescribing

*Generalized estimating equations controlling for history of fever and age, adjustment for repeated measures on the same day.

Site

Relative change in proportion of patients prescribed antimalarial

Antimalarial doses saved per

1000 patientsRR (95% CI)* p-value

Mubende 0.32 (0.29 – 0.36) <0.001 420

Jinja 0.44 (0.39 – 0.50) <0.001 358

Tororo 0.73 (0.70 – 0.77) <0.001 183Hopkins H, et al.

Satisfactory outcome at Day 5:- Improved on treatment prescribed at Day 0 and- Did not seek care elsewhere

Site

Proportion with satisfactory outcome at Day 5

p-valueNo RDTs(n = 682)

RDTs(n = 653)

Mubende 95% 96% 0.489

Jinja 93% 94% 0.845

Safety of non-treatment of RDT-negative fever in <5s

• Recruited febrile children aged 6 months to 10 years• Excluded gravely ill • RDT testing: no antimalarial if negative result. • Home visit at day 7• If ill before day 7, retest with RDT, reassess at day 14

300 febrile children (median age 2.5 years)

41 (14%) RDT+ 259 (86%) RDT -

3% loss to follow-up (moved/wrong address)

281/290 (97%) cured at day 7

286 (99%) cured at day 14

31/259 (12%) returned with fever (med 3.5d)

No new positive RDTs D'Acremont

2009 ASTMH

High mortality among patients admitted to hospital and treated for malaria

Admissions for malaria n=17,313Admissions for malaria n=17,313

Severe disease n=4670 (27%)Severe disease n=4670 (27%)

Readable slide results n=4474 (95%)Readable slide results n=4474 (95%)

No criteria forsevere disease n=12,643 (73%)120 deaths (1%)

No criteria forsevere disease n=12,643 (73%)120 deaths (1%)

Expert microscopy negativen=2412 (54%)

Expert microscopy negativen=2412 (54%)

Deadn=142 (7%)

Deadn=142 (7%)

Aliven=1920 (93%)

Aliven=1920 (93%)

Deadn=292 (12%)

Deadn=292 (12%)

Aliven=2120 (88%)

Aliven=2120 (88%)

Expert microscopy positiven=2062 (46%)

Expert microscopy positiven=2062 (46%)

Reyburn H

Malaria incidence in Livingstone District, Zambia

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ITN, IRS introduction

Phased introduction of RDTs

Impact of malaria RDTs on case reporting and ACT use

Senegal malaria case reporting

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% o

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RDT introduction

Map of malaria incidence

Polio case numbers

1988: 350,0001999: 7,1412000: 2,9792001: 483

Rapidly increasing range of malaria RDT products

Target Product Manufacturer Target Product Manufacturer Palutop Alldiag pLDH Core Malaria

Pv/Pf Core Diagnostics HRP2

dBest Ameritek OptiMal Diamed AG Rapimal Cellabs Malaria Test

Card International Immunodiagnostics

Immu-Sure Malaria

Brittney SD Bioline Malaria

SD Bioline

Malaria Test Bio-Analytics Falcivax Zephyr Biomedical Core Malaria Pf Core Diagnostics First Response Premier Medical Malar-Check Pf Cumberland FirstSign

Paraview Unimed

Assure Malaria Pf

Genelabs HRP2/pLDH Core Malaria Pan/Pv/Pf

Core Diagnostics

Smart Check Malaria

GlobaleMed Parascreen Zephyr Biomedical

Hexagon Malaria

Human Gmbh FirstSign Paraview Pan/Pv/Pf

Unimed

KatQuick KAT Medical Ag Combo Malaria Home Test Kit

Sanitoets

MakroMAL Makro Medical Malaria Test Fortress Visitect malaria

Pf Omega HRP2 /pan NOW-ICT Binax

Paracheck Orchid ICT Malaria Pf/pan-malaria

R&R Marketing

ICT Malaria Pf R&R Marketing MalaQuick r-Biopharm ParaHIT Span Diagnostics RapiCard

InstaTest Cortez

Uni-Gold Malaria Pf

Trinity Biotech Smart Check GlobaleMed

FirstSign Malaria Pf

Unimed One Step Bio-Quant Inc.

Malaria Pf Vision Biotech ParaHit Total Span Diagnostics Malaria Pf/Pv Vision Biotech

Figure 3: Maximum and Minimum Temperature in Center Medical store, Samplov Lun Operational

District and Ankor Ban Health Center in 2003

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Center Medical Store Sampov Lun OD Ankor Ban HC

Temperature oC

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CNM, MoH, Cambodia

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Sampour Lon HC

Temperature monitoring of RDT storage by MoH & WHO, Cambodia

RDT line intensity vs. storage time at 35C

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Operational issues RDT roll-out

• Procurement and distribution:– Test selection– Timely procurement distribution – Waste management – Return? Burn? Bury?

• Training and supervision:– Training in in case management, not just RDT testing– Retraining and monitoring

• QA/QC:– After purchase– After distribution– Integrate QA/QC systems for diagnostics not restricted to

malaria• Monitoring & evaluation:

– Result reporting for surveillance and for product vigilance– Integrate M&E across diseases– Electronic systems

• Private sector use

• Aim:To identify solutions to logistic and financial obstacles in the performance and availability of RDTs.

• Activities:– Jobs-aids bank and manuals for the transport and storage of RDTs. – Temperature monitoring with “LogTag” devices started in April 2009 in Senegal, Burkina Faso, Ethiopia,

Philippines.– Visit to Uganda of the School of Mines, University of Colorado for the design of a coolbox for RDT storage.– Survey on RDT distribution and prices in the private sector started in April 2009 in Senegal, Peru, Philippines,

Tanzania, Nigeria, CAR.– Project to assess the impact of RDTs use on rate of malaria cases and use of ACTs.

Obstacles to RDT implementation:Supply chain / Transport

Field evaluation of existing RDTs:Blood transfer devices / Pregnancy

• Aim:To contribute in the field performance of RDTs (training material, blood safety, and test use accuracy).

• Activities:– Assessment of the impact of long-term practices of health workers using RDT training material

on RDT performance. Zambia.– National Implementation Strategy and RDT regulatory guidelines in Uganda.– Improvement of blood transfer devices (accuracy, safety, and ease-of-use).– Utility of RDTs and LAMP as replacement of preventive treatment in pregnancy.

UgandaNigeria

SenegalBurkina Faso

Philippines

UgandaNigeriaPhilippines

Product testing is part of a larger FIND strategy for QA of malaria RDTs

Manufacturer

Supply chain management Transport and storage

End users-Appropriate training and instructions-Management of positive and negative results

Stage 1: Product testingEvaluate product performance

Stage 2: Lot testingConfirm product quality on arrival in country before dissemination to the field

Stage 3: PCWsEnsure health workers and patients that RDTs has maintained accuracy through transport and storage

Before purchase

Before distribution

Before use

• Aim:To establish a global specimen bank and regional capacity to support the development and evaluation of malaria diagnostics.

• Activities:Publication of the first FIND/WHO report on product testing of malaria RDTs in April 2009.Second round of product testing is ongoing and results expected before end of 2009.

Product testing with reference materials

Phase 2 Detection Rate for P. falciparum samples

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• Activities:Lot testing of RDTs in Cambodia, Philippines, and Ethiopia and capacity building in other countries.Characterization of recombinant proteins for future lot testing panel.

Lot Testing

IPC Lot-testing, Cambodia

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RECOMBINANT PANEL

HRP2 variants, Pf, Pv pLDH and aldolase

Positive Control Wells (PCWs): Quality control by health workers

• Aim:To provide capacity to test quality of RDTs in remote places and increase user’s confidence.

• Activities:PCWs stable at 60°C have been produced.Evaluation of thermostability at HTD and job-aids in Uganda in July 2009.