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
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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 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
Population living under intense transmission 0.016 0.375
ASIA AFRICA
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Counting & discounting populations at risk
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
Population living under intense transmission 0.016 0.375
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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Counting & discounting populations at risk
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
Population living under intense transmission 0.016 0.375
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
2015ESCMID eLibrary
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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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P. vivax chemotherapeutics
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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P. vivax chemotherapeutics
Blood schizontocidesQuinineChloroquinePiperaquineAmodiaquineMefloquinePyronaridineArtesunateDihydroartemisininArtemetherLumefantrine
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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P. vivax chemotherapeutics
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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P. vivax chemotherapeutics
• 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
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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
A great diversity of chemicalclasses, rare hemotoxicity in some
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P. falciparum chemotherapeutics
Blood schizontocidesQuinineChloroquinePiperaquineAmodiaquineMefloquinePyronaridineArtesunateDihydroartemisininArtemetherLumefantrineAtovaquoneProguanil
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P. falciparum chemotherapeutics
Blood schizontocidesPiperaquineAmodiaquineMefloquinePyronaridineArtesunateDihydroartemisininArtemetherLumefantrineAtovaquoneProguanil
Dihydroartemisinin-piperaquineArtesunate-amodiaquineArtesunate-pyronaridineArtesunate-mefloquineArtemether-lumefantrineAtovaquone-proguanil*ESCMID eLibrary
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Artemisinin-resistant P. falciparum
Roberts L. Science 2016 doi:10.1126/science.aaf9947
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Artemisinin-resistant P. falciparum
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Artemisinin-resistant P. falciparum
http://www.who.int/malaria/publications/atoz/artemisinin-resistance-august2018/en/
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Artemisinin-resistant P. falciparum
• 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
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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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A complex & unfolding story
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Other species not yet fully explored
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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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