Update on Malaria in Asia: Pervasive, Diverse, and ...

Update on Malaria in Asia: Pervasive, Diverse, and Invisible

Head of Unit

Eijkman-Oxford Clinical Research Unit

Eijkman Institute of Molecular Biology

Jakarta, Indonesia

&

Professor of Malariology

Centre for Tropical Medicine & Global Health

Nuffield Department of Medicine

University of Oxford

Oxford, United Kingdom

J. Kevin Baird, Ph.D., FASTMH

ECCMID April 2019Amsterdam, the Netherlands

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Plasmodial biology

Latency massively compliates biology, epidemiology, treatment and control

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The basics of malaria in Asia

• 2 billion Asians live at risk

• 7 species of parasites

• 28 species of important mosquito carriers

• Home to >85% of global P. vivax

• Rural poor most affected

• Urban malaria in Indian subcontinent

• Many millions of cases/year

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Global malaria in 2017C

ON

FIDEN

TIAL –

NO

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DISSEM

INA

TION

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NFID

ENTIA

L –N

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ISSEMIN

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Malaria transmission intensity in Asia lower than in Africa,

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Global population density in 2016

https://hanacaraka.co/population-density-world-map.html

but for more people at risk in densely populated AsiaESCMID eLibrary

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Asia’s invisible malaria

86% of deaths occurredbeyond the reach of healthcaredelivery services

WHO estimates <5% of malaria infections are reported in IndiaESCMID eLibrary

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Let’s look at numbers we can count

Population at risk of unstable malaria 1.03 0.05

Population at risk of stable malaria 0.66 0.75

Total population at risk of malaria 1.69 0.80

ASIA AFRICA

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Counting & discounting populations at risk




Population living under intense transmission 0.016 0.375

ASIA AFRICA

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Population not at risk of severe malaria 0.014 0.338(under intense transmission only infants, pregnant women and small children at risk)

ASIA AFRICA

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Population not at risk of severe malaria 0.014 0.338(under intense transmission only infants, pregnant women and small children at risk)

Total population at risk of severe malaria under stable transmission 0.646 0.412 billion

ASIA AFRICA

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Plasmodium vivax in Asia historicallydismissed as a cause of mortality

An intrinsically benign infection very rarely causing serious harm?

“Plasmodium vivax causes significant morbidity and mortality…”.

Risk of death with an admission diagnosis of vivax malaria relative to the same for falciparum malaria

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Malaria burden in Asia is invisible

H. sapiens

P. vivaxP. falciparum

Enormous uncertainty surroundingabsolute numbers of attacks and deaths

So also great uncertainty with proportionof burden between regions

Percent is (X/X+Y)X100, right?

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What magic gives us this “fact”

This trivialization of malaria burdens outside of Africa has no grounding in credible epidemiology

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What magic vanishes malaria in Asia?

No magic, but truly invisibleESCMID eLibrary

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http://asiamalariaimages.com

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P. vivax chemotherapeutics

RADICAL CUREESCMID eLibrary

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Blood schizontocidesQuinineChloroquine (1946)PiperaquineAmodiaquineMefloquinePyronaridineArtesunateDihydroartemisininArtemetherLumefantrine

HypnozoitocidesPlasmochin (1926)Primaquine (1952)Tafenoquine (2018)

All 8-aminoquinolinesAll cause acute hemolytic anemiain G6PD-deficient patients

A great diversity of chemicalclasses, rare hemotoxicity in some

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Chloroquine-resistant P. vivax

http://www.wwarn.org/vivax/surveyor/#0

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Blood schizontocidesQuinineChloroquinePiperaquineAmodiaquineMefloquinePyronaridineArtesunateDihydroartemisininArtemetherLumefantrine

HypnozoitocidesPlasmochin (1926)Primaquine (1952)Tafenoquine (2018)

All 8-aminoquinolinesAll cause acute hemolytic anemiain G6PD-deficient patients


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Blood schizontocides

Dihydroartemisinin +Piperaquine

Artemether +Lumefantrine

Hypnozoitocides

Primaquine

Logical and available therapies for radical cure of vivax malaria acquired in Asia

Good evidence of safety, tolerability & efficacy for DHA-PP +PQThat jury is out for AL+PQ

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• Two critical issues

– G6PD deficiency and hemolytic toxicity

– CYP2D6 polymorphisms and therapeutic efficacy

Both issues especially relevant in Asian context

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G6PD deficiency

Acute hemolytic anemia

An inherited metabolic defect – X-linked recessive

Plasmochin and primaquine confirmed to causefatal AHA when used as indicated in some patients

Tafenoquine severity unknown

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G6PD deficiency

Affecting 400 million people

In extraordinary diversity

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G6PD deficiency

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G6PD Screening

• X-linked recessive trait: hemi-, homo-, or heterozygous

• Lyonization and RBC mosaicism – females at risk mayscreen as “normal” in RDT format, require monitoring

• PQ Rx w/out screening but clinical monitoringacceptable – cease dosing with onset of AHA

• TQ Rx using qualitative RDT or clinical monitoring NOT acceptable – no retreat from single dose

• Quantitative screening necessary for TQ (>70% ofnormal activity)ESCMID eLibrary

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G6PD & 8-aminoquinolines

• PQ or TQ in G6PD unknowns exceedinglydangerous

• Clinical monitoring with PQ but not TQ mitigatesdanger

• Qualitative G6PD screening will clear femaleheterozygotes at risk of hemolysis for therapy

• Quantitative screening necessary for TQ (>70% ofnormal activity)

• Extent of harm possible with TQ is unknown

Beware late sudden onset of AHA – only after 3rd to 5th dose

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CYP2D6 polymorphisms impact PQ efficacy

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CYP2D6 polymorphisms impact PQ efficacy

Efficacy of primaquine hinges on naturally occurring CYP2D6 polymorphisms

This jury is out on tafenoquine

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CYP2D6 & 8-aminoquinolines

• PQ efficacy unequivocally CYP2D6-dependent

• CYP2D6 naturally highly polymorphic

• Impaired CYP2D6 alleles very common

• Impaired CYP2D6 likely overcome with higherdosing (completely safe in G6PD-normals)

• PQ therapy in null CYP2D6 metabolizersprobably futile at any dose

Therapeutic failure of high-dose, directly supervised PQvery probably due to impaired CYP2D6

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Plasmodium falciparum in 2017

Courtesy of Ros Howes, Malaria Atlas Project, Oxford U.NOT FOR PUBLIC DISSEMINATION

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P. falciparum chemotherapeutics

Blood schizontocidesQuinineChloroquinePiperaquineAmodiaquineMefloquinePyronaridineArtesunateDihydroartemisininArtemetherLumefantrine

GametocytocidesPlasmochin (1926)Primaquine (1952)

8-aminoquinolines, but do not cause acute hemolytic anemia as single low dose

Relevant in endemic areas nearingelimination


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Blood schizontocidesQuinineChloroquinePiperaquineAmodiaquineMefloquinePyronaridineArtesunateDihydroartemisininArtemetherLumefantrineAtovaquoneProguanil

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Blood schizontocidesPiperaquineAmodiaquineMefloquinePyronaridineArtesunateDihydroartemisininArtemetherLumefantrineAtovaquoneProguanil

Dihydroartemisinin-piperaquineArtesunate-amodiaquineArtesunate-pyronaridineArtesunate-mefloquineArtemether-lumefantrineAtovaquone-proguanil*ESCMID eLibrary

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• Efficacy of several ACTs severely eroded in theMekong subregion of SEAsia

• A rapidly deteriorating problem that should betreated as a global health urgency

• Greatly complicates therapeutic decisions formalaria acquired in SEAsia

• Newer therapies in the works, but none available today

Atovaquone-proguanil therapy should be considered for uncomplicated falciparum malaria in a traveler

returned from the Mekong of SEAsia

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“RDT-resistant” P. falciparum

• Most RDT based on histidine rich protein 2

• Most parasites express HRP2 and HRP3

• Mutant parasites may delete HRP2 and/orHRP3 without apparent cost to fitness

• HRP2/3 deleted mutants invisible to mostRDT

• LDH-based RDTs not yet impacted

A patient exposed to risk, presenting with malaria-like symptomsand testing negative with an HRP-based RDT should be presumed

to have malaria until more definitive diagnostics are performed

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Malaria zoonoses in Asia

Singh, B., & Daneshvar, C. (2013). Human Infections and Detection of Plasmodium knowlesi. Clinical Microbiology Reviews, 26(2), 165–184. doi:10.1128/CMR.00079-12

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The “other”human malarias

Prevalence usually <1% where endemic in Asia-Pacific but seen much more frequently using molecular diagnostics.ESCMID eLibrary

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Summing up

• Malaria burdens in Asia historically under-reported and trivialized in terms of numbers and benign species

• Vivax malaria may often threaten life and is exceptionally difficult to effectively treat

• Falciparum malaria in Asia is also dangerous and difficult to treat

• Though relatively infrequent, malaria caused by P. knowlesi, P. cynomolgi, P. ovale, and P. malariae are endemic in Asia and threaten any patient infected

The diagnosis of any malaria in a patient should be considered a clinical emergency.The notion of benign and malignant malarias discarded as dangerous dogma.

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Update on Malaria in Asia: Pervasive, Diverse, and ...

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