Uncomplicated Malaria and
Treatment
Jeanne Rini Poespoprodjo
Management of Malaria Training – Timika
25-28 March 2018
Plasmodium Species: infects human
• Plasmodium falciparum
• Plasmodium vivax
• Plasmodium malariae
• Plasmodium ovale curtisi
• Plasmodium ovale walikeri
• Plasmodium knowlesi
Transmitted by female anopheles bite
Free, unstable and stable risk areas were corresponded to PfAPI = 0 per 1,000 pa, 0, PfAPI, 0.1 per 1,000 pa and PfAPI$ 0.1 per 1,000 pa.
doi:10.1371/journal.pone.0021315.t002
Falciparum Malaria, Indonesia (2010)
Elyazar IRF et al, Plos One, 2011
Figure 3. The Plasmodium falciparum malaria PfPR2–10 endemicity map. Model-based geostatistical point estimatesof the annual mean PfPR2–10
for 2010 within the stable spatial limits of P. falciparum malaria transmission, displayed as a continuum of yellow to red from 0%–50% (see map legend).
132,8 million people are at risk of having falciparum malaria
The rest of the land area was defined as unstable risk (medium grey areas, where PfAPI, 0.1 per 1,000 pa) or no risk (light grey, where PfAPI = 0 per
1,000 pa).
Vivax malaria, Indonesia (2010) Vivax Malaria Endemicity in Indonesia in 2010
Elyazar IRF et al, Plos One, 2012
Figure 3. The Plasmodium vivax malaria PvPR1–99 endemicity map. Model-based geostatistical point estimates of the annual mean PvPR1–99 for
2010 within the stable spatial limits of P. vivax malaria transmission, displayed as a continuum of light green to red from 0% to 7% (see map legend).
129,6 million people are at risk of having vivax malaria
Areas within the stable limits in Figure 1 that were predicted with high certainty (. 0.9) to have PvPR1–99 less than 1% were classified as unstable areas
(shaded medium grey areas). The rest of the land area was defined as unstable risk (medium grey areas, where PvAPI, 0.1 per 1,000 pa) or no risk
(light grey, where PvAPI = 0 per 1,000 pa).
Female Anopheline
Life Cycle of Plasmodium
P. vivax forms hypnozoites in the hepatocytes that stay dormant: may relapsing
P. falciparum P. vivax
16-32 merozoites/schizont
12-24 merozoites/schizont
Fever Pattern..
Uncomplicated Malaria
Signs and Symptoms
Anamnesis:
• Fever, shivering, headache,
diarrhea
• Resides in malaria endemic
area
• History of travelling to malaria
endemic area: 1-4 weeks
before
Pemeriksaan Fisik:
Temp > 37.5 0C
Hepato + splenomegali + Apus Darah Malaria Positif
Pale….
NO SEVERE SIGNS
P. vivax Infections
White Malaria Journal 2011, 10:297
P. vivax phenotypes
P. vivax relapse pattern
Long latency P. vivax
Frequent relapse P. vivax
Frequent relapse + Long
Latency P. vivax
Relapse Interval: Determinants
• Number of sporozoites inoculations: more
sporozoites – more relapses
• Age: the role of immunity
– Relapses are less frequent in older individuals
• Antimalarial drug half life: long half life delay
relapses
Recurrences: within 63 days
• Recrudescence: high
parasitaemia
Pf • New infection: reinfection Pf
• Recrudescence: activation of Pv
hypnozoites
Pf • Simultaneous or near Pv
simultaneous
• Subpatent P. vivax parasitaemia
20-50%
P. vivax hypnozoites activation: systemic febrile illness
P. vivax recurrence following P.
falciparum/mixed infections
Pf treated with short half life drug: 53.8% had Pv recurrence in 63 days
Pf treated with long half life drug: 21.1% had Pv recurrence in 63 days
CID 2011:52 (1 March), Douglas et al
CID 2011:52 (1 March), Douglas et al
Late Recurrence: 12 months
Risk of Malaria Over
Subsequent Year Risk of Malaria Over
Pv
Mix Subsequent Year
Pf
Pm
Timika, 2004-2013
P. malariae
Slow replication
Low parasitaemia for a long time:
chronic
Proportion in Timika: 2.6% of all
malaria
Untreated: reported nephrotic
syndrome in children (low):
• chronic membranous
glomerulopathy and
mesangioproliferative
glomerulonephritis
• Non responsive to
corticosteroids
P. knowlesi
• Quotidian - 24 hour growth cycle for asexual
blood stages.
• Liver cycle is 5 days.
• Parasitemia can vary from low to high
• Fever and paroxysm can be mild to severe
Antimalarials for
Uncomplicated Malaria
• Each infections can consist of 2-3 asexual
cycles, each cycle take 48 hours (2 days)
Day 0 1 2 3 4 5 6 7-20 days
Infected asexual cycle Gametocytes
• 3 day Artemisinin treatment: dealing with 2
asexual cycles (Parasite reduction rate of 10,000)
• The slow acting partner drug is required to delay
the emergence of resistance
Treatment Goal
• Clear parasites and prevent progression to
severe disease
• Prevent antimalarial drug resistance
• Prevent transmission
Artemisinin Combination Therapy
(ACT)
ACT recommended by WHO:
• Artemether-lumefantrine
• Artesunate-amodiaquine
• Artesunate-mefloquine
• Artesunate-sulfadoxine pyrimethamine
• Dihydroartemisinin-piperaquine
Local Efficacy Studies
Uncomplicated Pf: Uncomplicated Pf:
• Day 42 Recrudescence rate: • Day 42 Recrudescence rate:
Art-Lum 2.4% [95%CI:0.4-4.4] Aq-As 13% [95%CI: 6-20]
DHA-Pip* 2.3% [95%CI:0.5-4.1] DHA-Pip 2.8% [95%CI: 0-5.9]
P=0.95 P=0.01
• Day 42 Reinfection rate: • Day 42 Reinfection rate:
Art-Lum 12% [95%CI: 8-16] Aq-As 11% [95%CI: 5.6-17]
DHA-Pip 9.6% [95%CI: 6.1-13] DHA-Pip 2.9% [95%CI: 1.6-5.6]
P=0.2 P=0.007
Uncomplicated Pv: Uncomplicated Pv:
• Day 42 Reappearance rate:
• Day 42 Reappearance rate: Aq+As 30% [95%CI: 22-38]
Art-Lum 37% [95%CI: 31-42] DHA-Pip 6.7% [95%CI: 2.4-11]
DHA-Pip 8% [95%CI: 4.9-12] P<0.001
P<0.001
Severe malaria
Artesunate iv had lower mortality
15% than quinine 22% p<0.0002
(Multicentre, Seaquamat group, 2005)
*Dihydroartemisinin Piperaquine Artesunate: rapid parasite clearance
Ratcliff et al Lancet, 369: 757-65, 2007 Hasugian et al CID, 44:1067-74, 2007
ACT for P.vivax malaria
Importance of Pharmacokinetic profile
Artesunate-
Amodiaquine
Artemether-
Lumefantrine
DHA- DHP
Piperaquine
Ratcliff et al Lancet, 369: 757-65, 2007 Hasugian et al CID, 44:1067-74,
2007
Universal Policy of ACT for Uncomplicated
Malaria
Indonesia DHA-Piperaquine
Vanuatu Artemether-Lumefantrine
Solomon Islands Artemether-Lumefantrine
PNG Artemether-Lumefantrine
Treatment Protocol
Kemenkes, 2009
• Uncomplicated P. falciparum and P. vivax malaria:
– First line: DHP (DHA 40 mg and PPQ 320 mg) for 3 days
• DHA 2-4 mg/kgBB/dose
• PPQ 16-32 mg/kgBB/dose
– Second line: Q7C7
– Primaquine:
• Pf single dose 0.75 mg base/kgBB
• Pv dan PO 0.25 mg base/kgBB for 14 days
• Bayi < 5 kgs:
– Q7C7
– Primaquine is not given to infants < 1 year old
• Severe Malaria:
– Artesunate (60 mg artesunate per vial) iv 2.4 mg/kgBB on 0, 12
and 24 hours and then every 24 hours until patient can tolerate
oral antimalarial drug (intravenous therapy should be minimal 24
hours)
– Continues with DHP/AAQ for 3 days
WHO 2010 and Kemenkes WHO 2015 and Kemenkes
2009 2017
Uncomplicated P. falciparum
and P. vivax malaria: Uncomplicated P. falciparum
and P. vivax malaria:
DHP (DHA 40 mg and PPQ 320
mg) for 3 days DHP (DHA 40 mg and PPQ 320
mg) for 3 days
• DHA 2-4 mg/kgBB/dose
• PPQ 16-32 mg/kgBB/dose • Children < 25 kg BW: minimum
DHA 2.5 mg/kg BW and PPQ 20
mg/kg BW per day
Infants < 5 kgs: Infants < 5 kgs:
– Q7C7 – DHP = 5 kgs infant’s
– Primaquine is not given to dosing
infants < 1 year old – Primaquine is not given to
infants < 6 months old
(unless G6PD status is
known)
WHO 2010 and Kemenkes WHO 2015 and Kemenkes
2009 2017
Primaquine:
Primaquine:
• Pf single dose 0.25 mg
• Pf single dose 0.75 mg base/kgBB
base/kgBB
• Pv dan PO 0.25 mg base/kgBB
• Pv dan PO 0.25 mg base/kgBB for 14 days
for 14 days Except for:
Except for: Pregnant women, Infants aged <
Pregnant women, Infants aged < 6 months old, Women
breastfeeding infants, G6PD
1 year old, Women breastfeeding deficient
infants’ G6PD deficient patient
G6PD deficient:
• Consider primaquine 0.75 mg/kg
BW once a week for 8 weeks
• Close medical supervision for
potential induced hemolysis
WHO 2010 and Kemenkes WHO 2015 and Kemenkes
2009 2017
Severe Malaria:
Severe Malaria:
• Artesunate (60 mg artesunate
per vial) iv 2.4 mg/kgBB on 0,
12 and 24 hours and then Children weight < 20 kgs:
every 24 hours until patient • Artesunate 3 mg/kg BW per
can tolerate oral antimalarial dose on 0, 12 and 24 hours
drug (intravenous therapy and then every 24 hours until
should be minimal 24 hours) patient can tolerate oral
antimalarial drug (intravenous
therapy should be minimal 24
• Continues with DHP/AAQ for 3 hours)
days
• Continues with DHP/AAQ for 3
days
Kemenkes
2017
Kemenkes, 2018
Primaquine Single Dose
Gametocydal in P.falciparum infection
Primaquine 14 Days
Radical Therapy for P. vivax infections
Anti -hypnozoites
• Total dose:
– 3.5 mg base/kg (0.25 mg/kg/day) or,
– 7 mg base/kg (0.5 mg/kg/day) for tropical
area/frequent relapsing vivax
• Maximum oral dose: 30 mg daily (2 tablets)
Obese patients treatment dosing
• Evidence on drug pharmacokinetic is lacking
• Risk of under-dosing
• Less drug is distributed in fats
• Use ideal/lean body weight
• Large patient but NOT Obese: use dosing per
mg/kg actual body weight
Artesunate
injection dosing
Malnourished Children
• Evidence on drug pharmacokinetic is lacking
• Diarrhea, vomiting, rapid gut transit, small intestinal
mucosal atrophy: may reduce oral drug absorption
• Hypoalbuminaemia: reduce protein binding, rapid drug
clearance
• Volume distribution may be larger, plasma drug
concentration may be lower
• Hepatic dysfunction: reduce drug metabolism
• However, not enough evidence to modify dose
• Use mg/kg body weight as normal nutritional status
children
Core Principles
1. Early diagnosis and prompt effective
treatment:
– Access to early diagnosis and treatment
within 24-48 hours after the onset of malaria
symptoms
2. Rational use of antimalarial agents
3. Combination therapy
4. Appropriate weight-based dosing
Thrombocytopenia
• Frequently found in vivax and falciparum
malaria: cam be < 20,000 cells/μL
• Immune mechanism to malaria: TNF α
• Rarely cause hemostasis disturbance
• Resolved following an effective malaria
treatment
• This is NOT a SIGN of Severity!
Thank You
