Plasmodium vivax: challenges in diagnosis,treatment, and elimination
Xavier Ding, PhD
Malaria Team Leader, FINDHUMAN‘s Expert Meeting, ASTMH 2018, New Orleans

Key Plasmodium vivax epidemiological figures• P. vivax and P. falciparum co-exist in most malaria endemic countries• P. vivax represents 4% of the estimated 216 million of malaria cases worldwide in 2016
• But 36% of all cases outside of sub-Saharan Africa (WHO) and 64% of them in the Americas

Estimated levels of Plasmodium vivax malaria endemicity within the limits of stabletransmission (https://map.ox.ac.uk)

Estimated country share of total P. vivax malaria cases(WHO)
2Key Plasmodium vivax epidemiological figures• In area co-endemic with P. falciparum, P. vivax incidence decreases more slowly than that of P. falciparum• P. vivax relative prevalence increases and is the main malaria species in a majority of countries
contemplating elimination.

WHO3

P. vivax has been a neglected malaria species for a long time
• Despite keeping a third of the world population at risk of infection, P. vivax has been neglected
for the past 60 years on the false assumption that this is a benign form of malaria.

•••

Single episode of P. vivax during the 1st trimester: risk of miscarriage increased four-fold (McGready et al., 2012)
P. vivax accounted for 3.1% of global spending in malaria research and development during 2007 to 2009 (PATH, 2011)
ADDITIONAL EVIDENCE OF SEVERITY AND NEGLECT“The weight of evidence now available leaves no doubt that vivax malaria in many settings often occurs inassociation with a pernicious and threatening course of illness, which does not assign cause and effect but instead,acknowledges real consequences without regard to their specific genesis.” (K. Baird, 2014)4

P. vivax is a very specific malaria with specific challenges
Sporogony occurs at lower
temperature
Elimination challenge

Hypnozoites(resting liver stage forms)
Rx and Elimination challenge
Early gametocytes and effective
transmission
Elimination challenge

low parasitemia
Dx challenge
The Lancet Infectious Diseases 2009 9, 555-566DOI: (10.1016/S1473-3099(09)70177-X)

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Similar to P. falciparum, asymptomatic infections are common
very low parasitemia
Dx challenge

Cheng et al. 20156P. vivax diagnosis challenges
106~100’000

105

Parasite / µl

104

Severemalaria

RDTs Microscopy PCR

P. vivax
parasitemia at
P. vivax inadmission
asymptomatic(symptomatics)~7’000

10’000103

Pointof care•

Microscopy• P. vivax often reported as P.
falciparum•

RDTs• P. vivax specific RDT rely on
the detection of Pv-LDH•~1’000

Only two P. vivax specificWHO PQ products

102
~200
10~10P. vivax
pyrogenic threshold~100
at best~50at best

Gap in point-of-carehighly sensitive
diagnostic

110-1
0.1
10-2

~0.02

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Potential answers“an improved RDT”
High-sensitivity RDT(HS-RDT)“a simplified PCR”
Loop mediated isothermal amplification(LAMP)
PCR
Excellent
performances
Lab format

RTD
Limitedperformances
POC format• HRP2-based RDT with a 10X
improved analytical sensitivity• Simple equipment and sample processing• No cold chain required, naked-eye read-out• No such RDT exist today for P.
• 60 µL of capillary blood
vivax but some are in development • LOD in the range of 1 to 5 p/µL

• Time to result is 1h• Commercial kit for P. vivax becoming available

8Analytical and clinical performances of a P. vivax specific LAMP kitSpecies

Parasitaemia(p/µL)

Pv-LAMP

Pan-LAMP+ reactions+ reactions• Analytical sensitivity evaluated using P.
vivax frozen whole blood samples atvarying parasitemia

P. vivax

20

6/6

6/6

P. vivax

106/6

6/6

P. vivax

56/6

6/6

• Samples at 5 p/µL are consistently
detected

P. vivax

15/6

3/6

P. vivax

0.53/6

5/6P. vivax

0.1

1/6

3/6

Negative blood

n/a

0/6

0/6

No template ctl*

n/a0/6

0/6

Negative ctl

n/a0/60/6

Positive ctl

n/an/a6/6

Laboratory evaluation at the Hosptial for
Tropical Diseases (UK)• Samples at 0.5 p/µL are detected in half
or more of all reactions• Analytical sensitivity appears similar tothat of the Pan-LAMP kit

Sonia M. Herrera et al. submitted

9Analytical and clinical performances of a P. vivax specific LAMP kit
SpeciesLaboratory evaluation at the Hosptial for
Tropical Diseases (UK)• Analytical specificity evaluated using a
range of Plasmodium species andmatching negative specimens• Pv-LAMP assay show perfect specificity

Sonia M. Herrera et al. submitted

Parasitaemia(p/µL)

P. falciparum~19,000
P. falciparum20
P. malariae
20
P. malariae
20
P. ovale
20
P. ovale
20
P. ovale
1,000
P. ovale
5,000
P. ovale
10,000P. knowlesi
350,000
P. knowlesi
350,000
Negative blood 1
n/aNegative blood 2
n/aNegative blood 3
n/aNegative blood 4n/aNegative blood 5n/a
Negative blood 6
n/aNegative blood 7Sonia
M. Herrera et al. n/asubmitted
No template ctl*
n/a

Pv-LAMP+ reactions

Pan-LAMP+ reactions

0/6
0/6
0/6
0/6
0/6
0/6
0/2
0/2
0/2
0/6
0/6
0/6
0/6
0/6
0/6
0/6
0/6
0/6
0/6

6/6
6/6
6/6
6/6
6/6
6/6
2/2
2/2
2/2
6/6
6/6
0/6
0/6
0/6
0/6
0/6
0/6
0/6
0/6

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Analytical and clinical performances of a P. vivax specific LAMP kit
Clinical evaluation in Colombia in collaboration with the Caucaseco Scientific Research Center

Sonia M. Herrera et al. submitted

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Analytical and clinical performances of a P. vivax specific LAMP kit
Retrospective Clinical evaluation in Peru

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P. vivax treatment challenges
Recommended treatment for Pv: CQ or ACT
Not much resistance, so less of a challenge than for Pf
Real challenge is Rx for hypnozoites:
PQ only option for 60 years
Now TQ coming up but same G6PD liability
Encouraged the development of better test for G6PDd, this wil facilitate the implementation ofradical cure Rx
No new anti relapse drug in the pipeline13

P. vivax elimination challenges
Hypnozoites:
Allow to bridge transmission seasons, explaining the geographical spreadof this species
Is the source of up to 95% of all blood stage infection: majority are
relapses
There is no Dx for hypnozoites
Wait for relapse and provide radical cure, but doesn’t prevent
transmission
Mass drug administration: costly, challenging, exposing 90% of target
population to unnecessary treatments
A Dx for hypnozoite would be ideal, FIND working on a serology based
approche in collaboration with I. Mueller
Robinson et al. 201514

Conclusions• P. vivax poses a number of very specific diagnosis, treatment, and elimination challenges• Better diagnostic tests for both clinical case management and elimination are required• A P. vivax specific LAMP commercial kit• will facilitate the identification of low density, asymptomatic infections• is best suited in countries approaching elimination• will complement existing kits for Pan detection and P. falciparum detection• The potential of LAMP for malaria not fully exploited:• High costs• Lack of clear recommendations and policy around highly sensitive diagnostics for malaria• Lack of implementation guidelines and case-study with demonstrated impact on
prevalence/transmission
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Acknowledgements

DFAT
Colombia
HTD
Eiken

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