Uncomplicated Malaria and

Treatment

Jeanne Rini Poespoprodjo

Management of Malaria Training – Timika
20-23 November 2017
 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:
• Day 42 Recrudescence rate:
Art-Lum 2.4% [95%CI:0.4-4.4]
DHA-Pip* 2.3% [95%CI:0.5-4.1]
P=0.95
• Day 42 Reinfection rate:
Art-Lum 12% [95%CI: 8-16]
DHA-Pip 9.6% [95%CI: 6.1-13]
P=0.2
Uncomplicated Pv:
• Day 42 Reappearance rate:
Art-Lum 37% [95%CI: 31-42]
DHA-Pip 8% [95%CI: 4.9-12]
P<0.001
*Dihydroartemisinin Piperaquine
Ratcliff et al Lancet, 369: 757-65, 2007
Uncomplicated Pf:
• Day 42 Recrudescence rate:
Aq-As 13% [95%CI: 6-20]
DHA-Pip 2.8% [95%CI: 0-5.9]
P=0.01
• Day 42 Reinfection rate:
Aq-As 11% [95%CI: 5.6-17]
DHA-Pip 2.9% [95%CI: 1.6-5.6]
P=0.007
Uncomplicated Pv:
• Day 42 Reappearance rate:
Aq+As 30% [95%CI: 22-38]
DHA-Pip 6.7% [95%CI: 2.4-11]
P<0.001
Severe malaria
Artesunate iv had lower mortality
15% than quinine 22% p<0.0002
(Multicentre, Seaquamat group, 2005)
Artesunate: rapid parasite clearance
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
2009
Uncomplicated P. falciparum
and P. vivax malaria:
DHP (DHA 40 mg and PPQ 320
mg) for 3 days
• DHA 2-4 mg/kgBB/dose
• PPQ 16-32 mg/kgBB/dose
Infants < 5 kgs:
– Q7C7
– Primaquine is not given to
infants < 1 year old
WHO 2015 and Kemenkes
2017
Uncomplicated P. falciparum
and P. vivax malaria:
DHP (DHA 40 mg and PPQ 320
mg) for 3 days
• Children < 25 kg BW: minimum
DHA 2.5 mg/kg BW and PPQ 20
mg/kg BW per day
Infants < 5 kgs:
– DHP = 5 kgs infant’s
dosing
– 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 0.75 mg • Pf single dose 0.25 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 <
1 year old, Women breastfeeding 6 months old, Women
infants’ G6PD deficient patient breastfeeding infants, G6PD
deficient

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
2009
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 2015 and Kemenkes
2017
Severe Malaria:
Children weight < 20 kgs:
• Artesunate 3 mg/kg BW per
dose 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
 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
Thank You