Report results Project/PoA Number: WPVNM0801739

Title of Activity:

Efficacy and safety of drug combination (dihydroartemisinine – piperaquine)

and artesunate tablet for the treatment of uncomplicated Plasmodium

falciparum malaria and chloroquine for the treatment of P. vivax malaria in 4

sentinel sites (Binh Phuoc, Dak Nong, Quang Tri and Ninh Thuan provinces),

Viet Nam in 2009.

Ta Thi Tinh, Huynh Hong Quang, Duong Cong Thinh, Nguyen Manh Hung and et al

September 2010

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1. Introduction:

In the last five years, there has been increasing concern about the emergence

of resistance to the artemisinin antimalarials in Southeast Asia. Several

publications including WHO reports include evidence for the presence of

P.falciparum resistance to artesunate on the Cambodia-Thailand border.

Preliminary information suggests that it may be present also in Myanmar, China.

Artemisinin, especially artesunate, have used extensively for malaria

treatment in Southeast Asia since around 1990, possibly even earlier on the Thai-

Cambodian border, in wartime. Since 1991, WHO has recommended the use of

artemisinin-based combination therapy in all areas where P.falciparum is

resistant to other antimalarial medicines to optimize therapeutic effectiveness and

delay the emergence of resistance? From 2006, WHO has advocated a complete

ban on artemisinin monotherapy for uncomplicated malaria?

The artemisinins are currently the most effective antimalarials available.

Their action is uniquely rapid; in some areas, especially in Southeast Asia, but

also in parts of East Africa, artemisinin-based combination therapy (ACT) is now

the only effective treatment for malaria. At a time when ACTs are being rolled

out all over the malaria endemic world and beginning to have an effect on

morbidity and mortality, also in tropical Africa, development and spread of

resistance would have extremely grave consequences for global malarial control.

In 2009, Ministry of Health (MoH) has promulgated the guidelines for Malaria Diagnosis and Treatment in Vietnam. According to the Guidelines, dihydroartemisinin- piperaquine (DHA-PIP) three days regimens are been recommended for the first – line and Quinine plus Doxycycline/clindamycine regimens are recommended for the second line treatment of falciparum malaria. Three-day Chloroquine regimen for vivax malaria and Artesunate monotherapy regimen have not used in Vietnam.

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In 2008, WHO already supported to monitoring of therapeutic efficacy surveys in four sentinel sites of Vietnam (Binh Phuoc, Gia Lai, Ninh Thuan & Quang Tri). The study had been performed from August to November 2008 (in Quang Tri) and from February to June 2009 in Binh Phuoc, Ninh Thuan and Gia Lai. The result showed that: three sites (Quant Tri, Gia Lai, Ninh Thuan) efficacy treatment is very high; especially DHA-PIP (ACT) regimen the cure rate is 100%. However, in Binh Phuoc the rate of ACPR is only 85%. Binh Phuoc province, where the artemisinin is used in 1980s, maybe P.falciparum is high tolerance with artemisinin. In fact, parasitemia is still 12% at D3, 5.7% at day 4 and 2.0% at day 7. Therefore, the regular monitoring of therapeutic efficacy surveys of antimalarial drugs is very important.

Fig 1: Therapeutic efficacy of antimalarial drugs in four sites in 2008

2. Methodology:

In vivo test 28 day is follow WHO protocol.

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2008Quang TriDHA – PIP

ACPR: 100%

2008Gia Lai

DHA – PIPACPR: 100%

2008Binh Phuoc

AS7DACPR: 85.4%LTF: 14.6%

2008Ninh Thuan

AS7DACPR: 97%LTF: 3%

3. Duration: From August 2009 to May 2010

4. Place of study and Drug: 4.1. Drug:

Dihydroartemisinin (40 mg) – piperaquin (320 mg) with commercial name is Arterakin. This drug is product of Central Pharmaceutical factory No. 1, Viet Nam, batch number: 1108, expiry date: 11/2011.This batch number has been certificate of analysis of Factory No1.

Artesunat 50 mg/tablet: Products came from Nam Ha Pharmaceutical factory, Vietnam. Batch number; 11207; expiry date: 12/2010This batch number has been certificate of analysis of Factory No1.

Chloroquine 250 mg/tablet: Chloroquine tablets will be provided by WHO (from Medopharm manufacturer, India. Batch number BMG126, expiry date August 2011.

4.2. Dosage:- Artesunate will be administered at the total dose of 16 mg/kgbw over 7

days (1st day: 4 mg/kgbw, 2nd to 7th days: 2 mg/kgbw/day). If patient can not measure, dosage of artesunat take by age groups as below table

Age group Number of artesunat tablets per dayDay 1 Day 2 - 7

< 1 year 1 1/21 - < 5 years 2 15 - < 12 years 3 1 1/212 - < 15 years 3 2

≥ 15 years 4 2

- Dihydroartemisinin – piperaquin (Arterakine) will be administered 3-day regimen, according to age groups. Correct drug dosage will be determined using the below table.

Age group Number of artesunate tablets per day0 hour 8 hour 24 hour 48 hour

≤ 3 years 1/2 1/2 1/2 1/23 - < 8 years 1.0 1.0 1.0 1.08 - < 15 years 1 1/2 1 1/2 1 1/2 1 1/2≥ 15 years 2.0 2.0 2.0 2.0

- Chloroquine : total dose: 25 mg base/ kgbw over 3 days D1 : 10 mg per kgbw

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D2 : 10 mg per kgbw D3: 5 mg per kgbw Doses of drug will given by the weight of the patients (Follow Protocol)

4.3 Study site: Binh Phuoc sentinel: the study site will be Dak Nhau commune, Bu Dang

district, Binh Phuoc province. This is a malaria hyper endemic commune with

24,800 hectares in area and population of 16,325 living on cashew, coffee and

pepper plantations and slash-and-burn cultivation, many of them are migrants

from other less malarious provinces. The commune health station (CHS) has

five persons including one medical doctor and one malaria microscopist.

Patients can access the CHS within 1 hour by local transportation (mainly by

motorbikes). Severe malaria cases will transfer to the district hospital 30 km

away, after receiving preliminary rescue treatment with parenteral artesunate.

In 2008, the study on efficacy and safety of artesunate tablet for treatment of

uncomplicated Plasmodium falciparum malaria supported by WHO have

carried out in this district. Bin Pruco site will have treated with two

antimalarial drugs: DHA- PIP (arterakin) for P.falciparum malaria and

chloroquine for P.vivax malaria.

IMPE Ho chi Minh is directly responsible this site

Ninh Thuan sentinel: Ma Noi commune, Ninh Son district, Ninh Thuan

province was placed this study. Ma Noi is located on the western of the Ninh

Thuan, far from Phan Rang city is about 50km, surrounded by forests and

mountains; in this region, the whole population exposed to risk of malaria.

Most of the inhabitants of this region are Raglei ethnic minority. Malaria

transmission is intense and continuous throughout the year in the area.

Parasite structure with 80% is P.falciparum, 20% is P.vivax.

IMPE Qui Nhon is directly responsible this site

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Dak Nong sentinel: The study site conducted in DakMilk district, Dak Nong

province. Dak Milk is located in the Northern of Dak Nong, 50 km far from

Gia Nghia town. Up to now, there is very few information on drug resistance

in this site. The malaria patients were treated DHA-PIP (arterakin) in this site.

NIMPE is directly responsible this site

Quang Tri sentinel: The study site conducted in Xy /Thanh communes,

Huong Hoa district, Quang Tri province; the site is located in the West of

Quang Tri, 130 km far from Dong Ha town. Malaria transmission is intense

and continuous throughout the year. In 2008, WHO already supported for

study on Efficacy and safety of drug combination (dihydroartemisinine –

piperaquine) for the treatment of uncomplicated Plasmodium falciparum

malaria. The data have shown that the rate of ACPR is 98.5% and LCF is

only 1.5%. Up to now, there are not any study in Quant Tri on efficacy and

safety of artesunate tablet.

IMPE Qui Nhon is directly responsible this site

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Fig 2: 4 sentinel sites in 2009

4.4 Data Analysis:- Excel sheet program (according to the Informal consultation on monitoring

P.falciparum and P.vivax resistance to antimalarial drugs in the Mekong regions, September 2007 instruction)

- Stata 8.0

5. Results:

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Binh PhuocDHA – PIP

CHL

Dak NongDHA - PIP

Quang Tri AS7D

Ninh ThuanCHL

5.1 Therapeutic efficacy for P.falciparum:

Table 1: Characteristics of P. falciparum patients before treatmentin three sentinel sites

 Quang Tri Dak Nong Binh Phuoc

Number of patient 75 37 59

Age (Mean ± SD)Under 5 (%)5 – 15 (%)Adult (%)

19.0 ± 13.99 (12%)

23 (30.7 %)43 (57.3 %)

25.4 ± 12.41 (2.7%)

5 (13.5%)31 (83.8%)

27.9 ± 10.4

2 (3.4%)57 (96.6%)

Males (%)Females (%)

42 (56 %)33 (44 %)

32 (86.5%)5 (13.5%)

52 (88%)7 (12%)

Temp. (0C) at Do (Mean ± SD) 37.5 0C (%)

38.7 ± 0.975 (100%)

38.8 ± 0.937 (100%)

38.4 ± 0.952 (88.1%)

Geometric mean density at Do (95% CI)

12,657(9,519 – 16,829)

18,199(12,517 - 26,462)

16,342(11,986 – 22,280)

Remark: - The number of samples in all sites is enough for analysis- Parasitemia of patients is not different significant in three sites.

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Table 2: Body Temperature and Parasitemiafrom D1 – D4 of P.falciparum patients in three sentinel sites

Quang Tri Dak Nong Binh Phuoc

Drug AS 7D DHA-PIP DHA-PIP

Fever at D1 (%) 34/75(45.3%)

8/37(21.6%)

24/59(40.7%)

Parasitemia at D1 (%)

47/75(62.7%)

17/37(46%)

39/59(66.1%)

Fever at D2 (%) 3/75(4 %)

0/37(0 %)

2/59(3.4%)

Parasitemia at D2 (%)

4/75(5.3%)

1/37(2.7%)

20/59(44%)

Fever at D3 (%) 2/75(2.7%) 0 1/59

(1.7%)Parasitemia at D3(%)

0 0 9/59(15.3%)

Fever at D4 (%) 0 0 1/59*

Parasitemia at D4(%)

0 0 1/59*

*patient was already changed quinine + doxycycline regimen Remark:- At D3, the parasite is clearance in all patients in Quang Tri (AS7D) and Dak

Nong (DHA - PIP regimen). However, in Binh Phuoc, 15.3% malaria patients have still parasitemia and one patient has fever. That mean one patient was classified ETF and changed second line drug (quinine + doxycycline).

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Table 3: Therapeutic efficacy of Artesunate (AS) and DHA+PIP for treatment of uncomplicated P.falciparum patients

No Site Drug Patient

s No

Completely follow up (before PCR) ACPR %

Corrected by PCR

LOSS and

WITHACPR ETF LTF/

LCF

1 Quang Tri

AS 7D 75 60 0 10 60/62

(96.8%) 13

2 Dak Nong

DHA-PIP 37 37 0 0 37/37

(100%) 03

3 Binh Phuoc

DHA-PIP 59 45 01 0 45/46

(97.8%) 13

Remark:- Dihydroartemisinin – Piperakin (arterakin) regimen is high efficacy, with the rate

of ACPR ís from 97.8% (in Binh Phuoc) and 100% (in Dak Nong). However, in Binh Phuoc, one case is ETF.

- Artesunate 7 day regimen in Quang Tri is high efficacy (ACPR = 96.8%). Many cases are recrudescence with P.vivax.

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5.2 Therapeutic efficacy for P.vivax:

Table 4: Characteristics of P.vivax patients before treatmentin two sentinel sites

 Ninh Thuan Binh Phuoc

Number of patient 67 35

Age (Mean ± SD)Under 5 (%)5 – 15 (%)Adult (%)

12.3 ± 11.79 (13.4%)

46 (68.7 %)12 (17.9 %)

31.4 ± 14.61 (2.9%)2 (5.7%)

32 (91.4%)Males (%)Females (%)

31 (46.3 %)36 (53.7 %)

25 (71.4%)10 (28.6%)

Temp. (0C) at Do (Mean ± SD) 37.5 0C (%)

38.8 ± 1.166 (98.5%)

38.5 ± 0.832 (91.4%)

Geometric mean density at Do (95% CI)

3,771(2,649 – 5,369)

6,310(4,810 – 8,224)

Remark: - The number of samples in all sites is enough for analysis.- The average age of malaria patients in Ninh Thuan is lower than in Binh

Phuoc. The rate of children was suffered from malaria in Ninh Thuan is very high.

- Parasitemia of malaria patients in Binh Phuoc is higher than in Ninh Thuan.

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Table 5: Body Temperature and Parasitemiafrom D1 – D3 of P. vivax patients in two sentinel sites

-Ninh Thuan Binh Phuoc

Drug CHL CHL

Fever at D1 (%) 32/67(47.8%)

10/35(28.6%)

Parasitemia at D1 (%) 53/67(79.1%)

25/35(71.4%)

Fever at D2 (%) 2/67(3%)

0/35(0%)

Parasitemia at D2 (%) 5/67(7.5 %)

8/35(22.9%)

Fever at D3 (%) 0 0

Parasitemia at D3(%) 0 0

Remark: - No malaria patients have fever and parasitemia at D3 in two sites.

Table 6: Therapeutic efficacy of chloroquine for treatment of P.vivax Malaria patients

No Site Patients No

Completely follow up (before PCR) ACPR %

Before PCR

LOSS and

WITHACPR ETF LTF/LCF

1 Ninh Thuan 67 57 0 04* 57/61

(93.4%) 06

2 Binh Phuoc 35 31 0 0 31/31

(100 %) 04

*4 recrudescence patients have not been analyzed by PCR

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6. Discussion: 6. 1 Efficacy of Artesunate to P.falciparum :

The results have shown that: the efficacy of articulate 7-day regimen to P.falciparum was still high in Quang Tri. The rate of ACPR is 96, 8% (corrected by PCR). No parasite is positive at day 3. In 2009, a study in Phu Then District, Gia Lai province is been supported by Global fund shown that: The rate of ACPR is 100%, and there is only one positive case at day 3. This data shown that efficacy of artesunate 7 day regimen to P.falciparum in Quang Tri, Gia Lai and Ninh Thuan in 2008 – 2009 is high. Only in Binh Phuoc (Dak Nhau commune, Bu Dang district), the rate of TF is 14.6% and the rate of positive parasite at day 3 is 12%. We can conclude that P.falciparum resists artemisinine in Dak Nhau, Binh Phuoc.

6.2 Efficacy of DHA – PIP to P.falciparum:The results have shown that the rate of ACPR of ACT regimen is 100% in

Dak Nong and 97.8% Binh Phuoc. Ten last years, reports on efficacy of DHA – PIP regimen to P.falciparum is always 100% in Viet Nam and parasite at day 3 is negative. Such as: 100% in Dak Nong (2006, 2008), 100% in Ninh Thuan (2008) and 100% in Quang Tri ( 2008). However, In Dak Nhau, Bu Dang, Binh Phuoc the rate of positive parasite at day 3 is 15.3%. This is most urgent that we operate to contain resistance artemisinine in this area.

6.3 Efficacy of chloroquine to P. vivax:In Binh Phuoc, the rate of ACPR of chloroquine to P.vivax is 100%. No

parasite is positive at day 3. But in Ninh Thuan, the rate of ACPR is 93.4%. There are four cases; parasite is recrudescence at day 28. Up to now, we could not analyze PCR to distinguish recrudescence or reinjection with P.vivax.

Ma Noi, Ninh Son, Ninh Thuan, this is hyper malaria endemic areas, the rate of malaria cases in children are 82.1%, and many cases are mix infection Pfalciparum and P.vivax. We think that four cases are recrudescence at day 28, that are may be reinjection.

Some reports have shown that P.vivax has still sensitive to chloroquine in Viet Nam.

7. Conclusion:

- The efficacy of DHA – PIP to P.falciparum has still high in Dak Nong in 2009, with the rate of ACPR is 100%, no parasite is positive at day 3.

- P.falciparum increases tolerance to DHA – PIP in Dak Nhau, Bu Dang, Binh Phuoc with 15, 5 positive parasites at day 3.

- The rate of ACPR of chloroquine to P.vivax is 100% in Binh Phuoc and 93.4% in Ninh Thuan (before corrected by PCR).

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8. Annex: Annex 1: Certificate of analysis of of chloroquine phosphate Annex 2: Certificate of analysis of DHA - PIP

Report submitted by: Dr Ta Thi TinhPrincipal Investigator (Viet Nam)

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