This document discusses malaria diagnosis and treatment in border areas and highlights several key points: 1) Accurate diagnosis is critical for effective malaria management but diagnosis can be challenging due to varying clinical responses to malaria infection. 2) Prompt treatment with artemisinin-based combination therapy (ACT) is important but drug resistance is a growing problem. 3) Attention should be paid to improving diagnosis through capacity building, equipment, and quality control as well as ensuring treatment is safe, effective, complies with guidelines, and is affordable.

1. MALARIA DIAGNOSIS AND
TREATMENT IN BORDER AREAS:
WHAT SHOULD WE PAY ATTENTION TO?
Asep Purnama
TC Hillers Hospital, Maumere, NTT

2. STRATEGIES
 Prevention
Vector control, Long Lasting Insecticide Net, Repellent etc
 Accurate diagnosis
 Prompt treatment with ACT
 Partnership
 Increase Coverage of Service
Erna Tresnaningsih, Direktur Pemberantasan Penyakit Bersumber Binatang, Depkes RI
Seminar Nasional Manajemen Malaria Terkini, Manhattan Hotel-Jakarta, 14 Juni 2008

3. MALARIA DIAGNOSIS
PROBLEMS

4. Clinical responses to malaria infection vary widely

5. CLINICAL MALARIA, BLOOD SAMPLE TAKEN
& POSITIVE DIAGNOSIS IN INDONESIA
3,500,000
3,000,000
2,500,000
2,000,000
1,500,000
1,000,000
500,000
0
8
00
01
02
03
04
05
06
07
'0
20
20
20
20
20
20
20
20
ar
M
n-
Ja
 Not all Malaria cases are diagnosed by microscopist or RDT
 Slide positive malaria cases don’t decrease significantly

6. M ALARIA KLINIS DAN PE E
M RIKSAAN SE DIAAN DARAH
M ALARIA DI JAWA BALI TAHUN 2000-2004
1600000 Klinis Pem SD
1475704
1400000
1200000
1210530
1000000
998791
800000 756833
600000
480048
400000
200000
0
2000 2001 2002 2003 2004
MALARIA KLINIS DAN
PEMERIKSAAN SEDIAAN DARAH MALARIA DI
LUAR JAWA BALI TAHUN 2000-2004
1974882
2000000 1702508 1732557
1686176 Kl i ni s Pem SD
1800000 1522831
1600000
1400000
1200000
1000000
404714 389477 337583 348366 479441
800000
600000
400000
200000
0
2000 2001 2002 2003 2004

7. S ED I A A N D A R A H M A L A R I A P OS I T I F
D A N M A L A R I A P f D A N M I X D I J A WA B A L I
TA H U N 2 0 0 0 - 2 0 0 4
120000
SD Positif Pf + mix
100000
80000
60000
40000
20000
0
2000 2001 2002 2003 2004
SED I A A N D A R A H M A LA R I A PO SI T I F D A N M A LA R I A Pf D A N
M I X D I LU A R JA W A B A LI
T A HU N 2 0 0 0 - 2 0 0 4
SD Posit if Pf + mix
200000 181315
155796 148478
150000 140769 132095
100000
50000
0
2000 2001 2002 2003 2004

8. MALARIA DIAGNOSIS
What should we pay attention to?
 Prompt and accurate diagnosis is critical to the
effective management of malaria
 Based on microscopic diagnosis/RDT
 Capacity building
 Equipment (microscope, RDT)
 Cost
 Quality Control

9. Survey of General Practitioner’s
Knowledge, Attitude and Practice on Malaria
in Sikka District, East Nusa Tenggara 2008
Jane Hidayat, Asep Purnama

10. MALARIA TREATMENT
PROBLEMS

11. P. falsiparum : chloroquine resistance
Countries with at least one study indicating chloroquine total failure rate > 20%
Countries with at least one study indicating chloroquine total failure rate > 10%
No recent data available

12. P. falsiparum:
Sulfadoxin-pyrimethamine resistance
Countries with at least one study indicating sulfadoxine-pyrimethamine total failure rate > 20%
Countries with at least one study indicating sulfadoxine-pyrimethamine total failure rate > 10%
Sulfadoxine-pyrimethamine total failure rate < 10%
No failure reported
No recent data available

13. P. vivax
prophylactic or treatment failure
P. vivax prophylactic or treatment failure

14. Anti Malaria Drug Resistance In Indonesia,
RESISTANCE OF PLASMODIUM TO
MALARIA DRUGS IN INDONESIA
1978 - 2003

15. SAFE & EFFECTIVE DRUGS

16. COMPLIANCE

17. COST

18. MALARIA TREATMENT
What should we pay attention to?
 Artemisinin based Combination Treatment
 Radical treatment is essential
 Outcome focus on clinical cure, parasitological
clearance, and blocking transmission
 Monitoring therapeutic efficacy of antimalarial drugs
based on clinical and parasitological responses (in-
vivo 28 days)

19. 74 countries have adopted ACTs Updated
1 Oct 2007
Continent Countries Drug Line
Burundi, Cameroon, Congo, Côte d'Ivoire, Democratic Republic of Congo, Eq. AS + AQ 1st
Guinea, Gabon, Ghana, Guinea, Liberia, Madagascar, Eritrea, Mali, Mauritania,
Senegal, Sao Tomé & Principe (ST&P), Sierra Leone, Sudan (S),
AFRICA Tchad, Zanzibar
Angola, Benin, Botswana, Burkina Faso, Central African Republic, Comoros, AL 1st
Ethiopia, Gambia, Guinea Bissau, Kenya, Malawi, Mozambique, Namibia, Niger,
Nigeria, Rwanda, Uganda, S. Africa, Tanzania, Togo, Zambia, Zimbabwe
Côte d'Ivoire, Djibouti, Gabon, Sudan (N), ST&P, Zanzibar AL 2nd
Djibouti, Somalia, Sudan (N) AS + SP 1st
Cambodia, Malaysia, Myanmar, Thailand AS + 1st
MQ
Bangladesh, Bhutan, Laos, Philippines, Solomon Islands, Sri Lanka, Vanuatu AL 1st
ASIA Indonesia AS + AQ 1st
Afghanistan, India, Iran, Pakistan, Saudi Arabia, Tajikistan, Yemen AS + SP 1st
Viet Nam, China DP 1st
Papua New Guinea AS + SP 2nd
Iran, Saudi Arabia, AL 2nd
SOUTH Ecuador, Peru AS + SP 1st
AMERICA Bolivia, Colombia, Peru, Venezuela AS + 1st
MQ
Brazil, Colombia, Guyana, Suriname AL 1st

20. INDONESIA’S TREATMENT POLICY
Uncomplicated Pf Complicated Pf
 ATS3+AQ3+PQ  QN parenteral-oral7+Dx7/Clin7
 DHP3+PQ  Artemether im-AQ3+ATS3
 QN7+DX7/Clin7+PQ  Artesunate iv-AQ3+ATS3
Uncomplicated Pv Prophylaxis
 ATS3+AQ3+PQ14  Doxycycline
 DHP3+PQ14
Outbreak containment (MFS)
 QN7+PQ14
 AQ3+ATS3+PQ1

21.  Since 2004 Artesunate-amodiaquine as the first line
ACT for P.falciparum malaria (based on the African
study Adjuik M et al, Lancet 2002).
 Efficacy of Artesunate-amodiaquine varied between
study sites 78-96% (Gasem H et al, 2004 ; Tjitra E et al, 2004; and
Sutanto I et al, 2004; Setyoningrum E et al, 2005; Hasugian et al, CID 2006 ).
 Utility of Artesunate-amodiaquine reported low (<50%)
due to poor compliance and adherent events because
of need to take large number of pills (personal
communication)

22. ASSESMENT OF CHLOROQUINE AND ARTESUNATE-
AMODIAQUINE COMBINATION EFFICACY FOR THE
TREATMENT OF UNCOMPLICATED FALCIPARUM MALARIA
IN BELU DISTRICT, EAST NUSA TENGGARA
Asep Purnama et al, IJIM 2006:38;327-31

23. RESULTS
 Due to an increase in the chloroquine treatment failure rate
to 47,62%, recruitment was terminated prematurely
 A total of 95 of the originally recruited 203 patients were
enrolled in the study
 Artesunate-amodiaquine showed superior 28-day cure rate
 Chloroquine versus artesunate-amodiaquine was 22/42
[52,38%] versus 49/53 [92,45%]; p<0,01
 However , efficacy of As+Aq was <95%, below than WHO
standard

24. ARTESUNATE - AMODIAQUINE VERSUS CHLOROQUINE
FOR THE TREATMENT OF VIVAX MALARIA
IN MAUMERE, EAST NUSA TENGGARA
National Institute of Health Research and
Development, MOH, Jakarta

25. RESULTS
 A prospective comparative clinical trial of efficacy, safety
and tolerability of As+Aq versus chloroquine for treatment
of uncomplicated vivax malaria with a 28-day follow up
 Of a total 105 enrolled patients there were 100 patients
could be analysed
 The efficacies of As+Aq and Chloroquine were 88% and
40,8% on day 28 by ITT and 93,2% and 47,2% by
PP, respectively
 However , efficacy of As+Aq was <95%, below than WHO
standard

26. NEED ALTERNATIVE ACTs
ATS3+AQ3 QN7+Dx7/Clind
 Efficacy <95% (Papua 70-87%)  Efficacy ?
 AR: nausea and vomiting  AR: dizziness, tinnitus
 Compliance? (no of pills)  Poor compliance
 Cost and accessibility?

27. IMPROVING ACT
COMPLIANCE CURE RATE
 Effective: rapid
 Tolerate: tasteless
 Safe: risk groups (infancy
broad spectrum
 Practice : all species
and pregnancy)
adverse events single dose only
 Simple: fixed-dose regimen
all age groups
single daily dose/
single dose only

28. CLINICAL TRIALS ON ACTs
(ATS+PD)3
(ART+NTQ)1 VS
Parentral ATM vs QN
ATS3+AQ3 VS (DHA+PPQ)3
(ART+PPQ)2
(ATS+PD)3 vs
((ATM+LMF)3
CQ3 vs (CQ3+SP1) vs AQ3
IV ART vs QN
(ATS+PD)3 vs
(ART+NTQ)1 VS
((CQ)3 (ATM+LMF)3 VS
(DHA+PPQ)3
(ATS+PD)3 vs (DHA+PP)Q3
((ATM+LMF)3 ATS3+AQ3 VS
(DHA+PPQ)3

29. EFFICACY COMBO VS FIXED REGIMEN
N=352
Artesunate+amodiaquine (ATS3+AQ3) vs Artemisinin+piperaquine (ART+PPQ)2
Pf: 93.8% vs 96.5% Pv:96.5% vs 100% (Tjitra E et al, 2005)
4
7
3.5
6
3
5
2.5
4
2
3
1.5
2 1
1 0.5
0 0
Day 0 Day 1 Day 2 Day 3 Day 7 Day 14 Day 21 Day 28 Day 0 Day 1 Day 2 Day 3 Day 7 Day 14 Day 21 Day 28
ATS3+AQ3 ART2+PPQ2 ATS3+AQ3 ART2+PPQ2

38. Artemisinin/naphtoquine P. vivax,
P. falciparum, P.mix phase III trial
A Phase III randomized, open label, non-inferiority trial
of artemisinin plus naphtoquine (ARCO) versus dihydroartemisinin
plus piperaquine in adult uncomplicated malaria patients: A Multi-
centre study in Indonesia

39. Artemisinin/naphtoquine phase III trial
Study outline
 401 patients randomized
 Study duration: April 2007 – August 2008
 Treatment : single dose, F/U to 42 days
 Multicentre: 2 sites, 4 hospital
 :

40. Artemisinin/naphtoquine phase III trial
Conclusions
 The trial demonstrated non inferiority treatment study
 Arco vs Duocotecxin
 P. vivax 98,7% vs 97,3%
 P. falciparum 98,7% vs 97,1%
 Both new fixed-dose ACTs are confirmed very
effective, safe and tolerate for treatment of any malaria in
adults, and meet with the recent WHO recommendation for
replacing ineffective drugs

41. ARTEMISININ FOR SEVERE MALARIA
ARTEMETHER QUININE DIHYDROCHLORIDE
 FCT= 35.5 hours  FCT= 37.4 hours
 PCT= 38.9 hours  PCT= 41.8 hours
 Regain consciousness=  Regain consciousness =
32 hours 62.8 hours
 CFR cerebral mal =  CFR cerebral mal = 71.4%
37.5%  Overall CFR= 23%
 Overall CFR= 13%
Tjitra E et al, MJI, 1996

42. SEAQUAMAT TRIAL
 Study design: Open label, multi centre,
randomised, comparison of artesunate
and quinine in severe falciparum
malaria
 Study sites: 2003-2005
 Bangladesh
 Indonesia (Timika Hospital, Timika)
 India
 Myanmar
 Target sample size: 2,000 patients
 1400 enrolled as at February 2005
 Coordination: Wellcome Unit, Bangkok

43. RESULTS
(SEAQUAMAT Group, Lancet, 2005)
 Trial stopped early (n=1461) by Safety Monitoring
committee because clear benefit with artesunate
 Overall reduction in mortality with artesunate 34.7%
(95%CI 19-48%) p=0.0002
 mortality quinine: 164/731 (22%)
 mortality artesunate: 107/730 (15%)
 Indonesian national policy change before the results
published
 Australian policy change 2006

44. THE IMPORTANCE OF COOPERATION BETWEEN
NEIGHBOURING COUNTRIES
 Many health problems are cross border
(malaria, rabies, filaria, DHF etc)
 Limited resource: mutual cooperation important
 Potential for inefficiency if countries work alone
 Sharing expertise and facilities
 Cooperation on research projects
 Share results of individual research
 Cooperation to develop guidelines or policy

52. MASS BLOOD SURVEY-YASPEM
 Target 45.454 [3 kecamatan]
 Blood sample taken 37.974 83,48 %
 Results F 351 0,9 %
V 517 1,4 %
Mix 71 0,2 %
Total 939 2,5 %

53. DROP OUT
 Adverse event 18 [1,9%]
 Hospitalized 6 [0,6%]
 Loss of follow up 8 [0,8%]
 Reject to take medicine 12 [1,3%]

54. SOME EXAMPLES OF POOR PRACTICE
• Giving SP to patients with fever even though blood
smear negative
• Treating uncomplicated malaria with parenteral quinine
or arthemeter im
• Treating complicated malaria with chloroquine or ACT
• Giving SP for P vivax malaria
• Giving Primaquine 15 mg for 14 days for P falciparum
malaria
• Giving all available forms of treatment to the one
patient

55. SOME EXAMPLES OF POOR PRACTICE (contd)
• Using RDT to evaluate response to treatment
• Giving transfusion to malaria patients with mild
anaemia
• Using steroids to treat cerebral malaria
• Inadequate fluid for complicated malaria
• Postponing haemodialysis for complicated malaria
with acute renal failure
• Unawareness of hypoglycemia in complicated malaria
• Not giving ACT for 3 days
• Giving inadequate doses of artesunate or arthemeter