Faculty of Medicine, Universitas Sumatera Utara

ANTIMALARIAL
EFFICACY IN
INDONESIA
Inke Nadia D. Lubis

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Outlines
• Malaria situation in Indonesia
• Antimalarials and malaria global burden
• Artemisnin combination therapies (ACTs) and emergence of resistance
• ACTs efficacy in Indonesia
• North Sumatera study
• Triple ACTs
• Drug resistance markers

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Malaria situation in Indonesia

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Antimalarials

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Malaria burden worldwide

2004:
1990s: ACT is
1970s: Mefloquine recommended
Resistance resistance
to SP
1970s:
Chloroquine
resistance in
all continent

1950s: 1969:
Chloroquine Eradication
resistance efforts
emerged halted

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Spread of chloroquine resistance

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Spread of SP resistance

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Artemisinin-combination therapies (ACTs)

• Artemisinin or qinghaouse from Artemisia annua was discovered in 1970s
• Acts against all Plasmodium species and effective against sexual and asexual stages

• It is combined with a partner drug with a longer half-life to:

– Ensure clearance of remaining parasites
– Prevent development of resistance

• Artemether-lumefantrine (AL)
• Artesunate-amodiaquine (ASAQ)
• Dihydroartemisinin-piperaquine (DP)
• Artesunate-mefloquine (AS-MQ)
• Artesunate-sulfadoxine pyrimethamine (AS-SP)

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Emergence of ACT resistance

Frequency distribution of the wild-type K13 allele in Asia

• In Southeast Asia, there is a threat of Plasmodium

falciparum resistance to artemisinin and its partner
drugs evidenced by:
– A markedly slower parasite clearance (increased
day 3 positivity)
– Some proportion of recrudescences at day 42

Menard D, NEJM 2017

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ACTs efficacy for P. falciparum infection

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Definition of artemisinin resistance

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Proportion of treatment failures

with ACTs across Indonesia
In Indonesia:
• ASAQ (2004 – 2012)
• DP was used:
– Eastern Indonesia from 2007
– Western Indonesia from 2012
• AL is available in the private
sector

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Proportion of treatment failures

with ACTs across Indonesia
In Indonesia:
• ASAQ (2004 – 2012)
• DP was used:
– Eastern Indonesia from 2007
– Western Indonesia from 2012
• AL is available in the private
sector

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North Sumatera study, 2015

Dihydroartemisnin-Piperaquine vs Artemether-Lumefantrine

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Parasite clearance by qPCR

Mean parasite clearance times in DP
and AL were 1.6 and 1.9 days,
respectively.

Factors associated with qPCR day 3

positivity:
• Living in South Nias (OR 1.37)

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Day-42 PCR uncorrected efficacy

T re atment Da y of S pe cies at day of failure
f a ilure by PCR
DP 3 P. falciparum , P. malariae
7 P. falciparum
7 P. malariae
14 P. malariae
14 P. malariae
14 P. knowlesi
21 P. malariae
42 P. malariae
AL 14 P. knowlesi
35 P. falciparum, P. vivax, P.
malariae

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Day-42 PCR corrected efficacy

11 year-old girl, South Nias, treated with DP Initial

parasite density of 1,120 p/μL.

At day 3, parasite was 1,240 p/μL.

Msp1, msp2 and glurp genotyping confirmed true

recrudescence à Early treatment failure
a b
Sampled day Pfcrt Pfmdr1 Pfk13 Pfmdr1 CN
Day 0 SVMNT YYD WT Multi copy
Day 1 SVMNT YYD WT NA
Day 2 SVMNT YYD WT NA
Day 3 SVMNT YYD WT Multi copy
Day 7 SVMNT YYD WT Single copy

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Day-42 subpatent recurrences

Factors associated with subpatent

recurrences:
• Living in Langkat (HR 3.28)

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Triple ACTs
• Triple combination therapies?
– Using two partner drugs with artemisinin (TACTSs)
– To sustain efficacy of the drugs over longer period
– Partner drug has to provide mutual protection, and mechanisms of resistance to either
drug must at least be distinct

• TRAC II study in Thailand, Cambodia and Vietnam – DP failed in 50% patients

– DP + MQ efficacy was 98%
– Safe and tolerated
– Other combination ASAQ + AL

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Drug Resistance Markers

• Tools to detect and monitor the presence of antimalarial resistance
• Geographically map the extent of resistant-parasites
– Strategies to control and eliminate malaria

• Pfcrt gene (codon 72-76) - chloroquine resistance

– Haplotype CVMNK (wild-type), CVIET (CQ-resistant from Africa and SEA), SVMNT (CQ-resistant from
South America and Asia)
• Pfmdr1 gene (codon 86, 184, 1034, 1042, 1246) – chloroquine resistance
– Haplotype 86, 184, 1246 YYY (amodiaquine resistant), NFD (artemether-lumefantrine resistance)
– Amodiaquine resistance occurred when combined with Pfcrt SVMNT

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Indonesia

2003 2003
2003 2003
2003 2003
2003
2000
2003 2003

Pfcrt
2002
2007 Pfmdr1
Pfdhfr
Pfdhps
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Marker for artemisinin resistance – K13

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Marker for piperaquine resistance

Plasmepsin copy numbers

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Clinical Study in North Sumatera

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Pfcrt & Pfmdr1 polymorphisms

Pfcrt 72-76 Pfmdr1 86/184

n=71 n=92

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Pfk13 polymorphisms
T474A

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Post-treatment parasite selection

Occurrence of
Pfmdr1 DP AL
N86/184F
Day 28 versus OR 36.6, OR 24.4,
baseline 95% CI 6.9-235.4, 95% CI 4.4-
P=0.0001 237.2, P<0.0001
Day 42 versus OR 13.1, OR 28.6,
baseline 95% CI 2.7-81.4, 95% CI 5.1-
P=0.0001 277.7, P<0.0001

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ACTs efficacy to other Plasmodium spp.

• Superiority of DP compared to AL, ASAQ and. AS-SP for treating P.

vivax, but similar efficacy with AS-MQ Visse BJ, Malar J 2014
• In Indonesia, high efficacy for P. vivax except in one study from
Papua with 48% recurrences Ratcliff A, Lancet 2007; Price RN, AAC 2007; Hasugian AR, CID 2007;
Pasaribu AP, JID 2013

• ACT is also effective against P. malariae and P. ovale Visse BJ, Malar J 2014
• Against P. knowlesi, AS-MQ, AL and DP are effective against
knowlesi malaria

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Conclusions
• ACTs is the current recommended therapy for falciparum malaria, and as in Indonesia
also for other Plasmodium spp.

• Despite increasing reports of resistance to artemisinin in Greater Mekong subregion, no

evidence of artemisinin resistance in western Indonesia
– Pfk13 T474A mutant parasites à in 4% patients but not associated with day 3 positivity

• High frequency of parasites carrying pfcrt-SVMNT and pfmdr1 86Y/184Y:

– Chloroquine and amodiaquine resistance
– High sensitivity to lumefantrine and artemisinin

• DP and AL remain effective for the treatment of uncomplicated falciparum malaria in

North-Western Indonesia
– Recurrences with P. malariae (70%) were frequent
– High proportion of subpatent P. falciparum recurrences at days 28 and 42,
with both DP and AL select parasites carrying pfmdr1 N86/184F
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Thank You

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Treatment Outcomes
Early Treatment Failure
• Danger signs or severe on day 1, 2 or 3 in the presence of parasitaemia
• Parasitaemia on day 2 higher than on day 0, irrespective of axillary temperature
• Parasitaemia on day 3 with axillary temperature > 37.5 ⁰C
• Parasitaemia on day 3 > 25% of count on day 0
Late Clinical Failure
• Danger signs or severe malaria in the presence of parasitaemia on any day between day 4 and day 28 (day
42) in patients who did not previously meet any of the criteria of early treatment failure
• Presence of parasitaemia on any day between day 4 and day 28 (day 42) with axillary temperature > 37.5
⁰C (or history of fever) in patients who did not previously meet any of the criteria of early treatment failure
Late Parasitological Failure
• Presence of parasitaemia on any day between day 7 and 28 (day 42) and axillary temperature < 37.5⁰C in
patients who did not previously meet any of the criteria of early treatment failure or late clinical failure
Adequate Clinical and Parasitological Response
• Absence of parasitaemia on day 28 (day 42) , irrespective of axillary temperature, in patients who did not
previously meet any of the criteria of early treatment failure, late clinical failure or late parasitological
fk.usu.ac.id failure