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 Specific research studies
Assessment of drug efficacy of dihydroartemisinine - piperaquine and chloroquine in treatment for uncomplicated Plasmodium falciparum and Plasmodium vivax malaria respectively in Central highland region

Abstracts

Background: The parasite resistance to antimalarial drugs in Central highland of Vietnam is an early warning to us that we are losing the most optimal weapons fighting the malaria. The dihydroartemisin plus piperaquine combination and chloroquin, which was listed into the essential antimalarial drugs since 2007 in Vietnam, has been used for 10 years until resistance appears in some Southern, Central of Western highland provinces.The study was conducted to evaluate the first-line drugs' efficacy in the treatment of uncomplicated Plasmodium falciparum and Plasmodium vivax patients in multicenters;

Methods: With the non-randomised controlled study design, minimum sample size, sampling, duration of follow-up, and classification of responses to treatment outcomes (WHO, 2009) in line with WHO?s protocol (2009).

Results: For DHA-PPQ regimen to P. falciparum malaria, ACPR in 3 sentinel sites were absolute cure rate (100%), except for Gia Lai sentinel with the ACPR after corrected-PCR of 95%, LCF of 1.29% and ETF of 3.71%. PCT and progression was within 48 hours o­nly; except for some cases in Gia Lai was positive asexual parasite in day 3 or ? 72 hours. The proportion of positive D3 of 17% as clinical marker for suspected resistance. The efficacy CQ was still maintains at absolutely high level to P. vivax malaria patients, and the ACPR were 100% in 3 sentinel sites, good tolerance of DHA-PPQ and CQ was found in the treatment regimens.

Conclusions: Both DHA-PPQ and CQ regimens were highly efficacious; however, the weakness include LCF (1.29%), ETF (3.71%), and high rate of parasite existence in D3 day (17%) in DHA-PPQ regimen as an indicator of drug resistance. Therefore, these cases should be more analyses of pharmacokinetics aspect, molecular markers to confirm the resistance more thoroughly.

Key words: Dihydroartemisinin-piperaquin, chloroquine, efficacy, resistance

 

INTRODUCTION

The parasite resistance to artemisinins along the Thai-Cambodia border area in the last five years is an early warning to us that we are losing the most optimal weapons fighting the parasites. Vietnam shares a border line with Cambodia, where P. falciparum is proven highly resistant to chloroquine, mefloquine, quinin and reduced responsive to various currently used drugs, including artesunate. Confronted with the warning signs, the WHO has recommended world countries to switch to the artemisinin combination therapies (ACTs). The dihydroartemisin plus piperaquine combination, which was listed into the essential antimalarial drugs since 2007 in Vietnam, has been used for 5 years until resistance appears in some Southern, Central of Western highland provinces.

Additionally, chloroquine (CQ) has long been used in Vietnam as a multi-purpose drug such as prophylaxis and treatment for both P. falciparum and P. vivax malaria for almost 60 years. Although there haven?t been any reports of CQ resistance by P. vivax in the Central highland region; many studies in the Southeast Asian countries have found resistance of the parasite to the drug at different levels. Therefore, it is necessary to evaluate the efficacy of the antimalarial drugs to contribute to the data accomplishment and to propose malaria treatment regimens that fit into the current situation and base as fundamentals for designing the national dug policy in the future. The study was conducted with objectives:

1.To evaluate the drug efficacy of dihydroartemisinine-piperaquine in the treatment of uncomplicated Plasmodium falciparum patients;

2.To evaluate the drug efficacy of chloroquine phosphate in treatment of Plasmodium vivax patients.

2. SUBJECTS AND METHODS

2.1. Locations and timing of study

The study was conducted in multi-centers in malarial hyperendemic areas at: Phu Thien district (Gialai province), Thuan Bac district (Ninh Thuan province), and Huong Hoa district (Quang Tri province) from the years 2011 to the end of 2012.

2.2. Subjects and materials

2.2.1. The uncomplicated P. falcipparum malaria patient?s group

Inclusion criteria

-Age between 6 months to under 70 years old;

-Mono-infection with P. falciparum detected by light microscopy;

-Parasitaemia of1.000 - 100.000 asexual forms/l blood;

-Presence of axillary temperature ? 37.5C or history of fever (past 24h);

-Ability to swallow oral medication;

-Ability and willingness to comply with the study protocol for the duration of the study and to comply with the study visit schedule;

-Informed consent from the patient or parents in the case of children;

-Not yet take any antimalarial drugs.

Exclusion criteria

-Presence of general danger signs in children aged under 5 years or signs of severe falciparum malaria;

-Mixed or mono-infection with another Plasmodium species;

-Presence of severe malnutrition, febrile conditions due to diseases other than malaria (acute lower respiratory tract infection, severe diarrhoea) or other known underlying chronic or severe diseases, severely vomitting, or psychological disorders;

-History of hypersensitivity reactions or contraindications to any of the medicine(s) being tested;

-A positive pregnancy test or breastfeeding women;

2.2.2. The P. vivax malaria patient?s group

Inclusion criteria

-Age over 6 months to < 70 years old;

-Mono-infection with P. vivax detected by light microscopy;

-Parasitaemia ofasexual forms ? 250/l blood;

-Presence of axillary temperature ? 37.5C or history of fever (past 48h);

-Ability to swallow oral medication;

-Ability and willingness to comply with the study protocol for the duration of the study and to comply with the study visit schedule;

-Informed consent from the patient or parents in the case of children;

-Not yet take any antimalarial drugs.

Exclusion criteria

-Under 6 months or ? 70 year olds;

-A positive pregnancy test or breastfeeding women;

-Presence of general danger signs in children aged under 5 years or signs of severe vivax malaria;

-Presence of severe malnutrition, febrile conditions due to diseases other than malaria (acute lower respiratory tract infection, severe diarrhoea) or other known underlying chronic or severe diseases, severely vomitting, or psychological disorders;

-Mixed or mono-infection with another Plasmodium species.

2.2.3. Antimalarial drugs to be tested in clinical trials

-Arterakine tablet (40mg dihydroartemisinin plus 320mg of piperaquin phosphate).Dosage regimen as followed:

Dosage by

Dosage in 3 days regimen

Age group

Body weight

0h

8thh

24thh

48thh

< 3 years

< 15 kg

3 - < 8 years

15 - < 24kg

1

1

1

1

8 - < 15 years

25 - < 34kg

1

1

1

1

? 15 years

? 35kg

2

2

2

2

-CQ 250mg tablet (150 mg base) with 3-day regimen as followed by day 1 (10mg base/kg bw), day 2 (10mg base/kg), and day 3 (5mg base/kg).

2.2.4. In code in patient?s clinical trials

-QTAK as Quang Tri arterakin, QTCQ as Quang Tri chloroquin ;

-NTAK as Ninh Thuan arterakin, NTCQ as Ninh Thuan chloroquin;

-GLAK as Gia Lai arterakin, GLCQ as Gia Lai chloroquin.

2.3. Study methods

2.3.1. Study design: Non-randomised controlled study design.

2.3.2. Sample size

Classical statistical methods are recommended for determining sample size, o­n the basis of an expected proportion of treatment failures, desired confi­dence interval (95%) and precision (10%).

In the DHA-PPQ regimen versus P. falciparum

In the case of a medicine with an expected failure rate of 20%, a confidence interval of 95% and a precision level of 10%, a minimum of 61 patients should be enrolled.

In the CQ regimen versus P. vivax

In the case of a medicine with an expected failure rate of 10%, a confidence interval of 95% and a precision level of 10%, a minimum of 35 patients should be enrolled

Estimated population proportion (p), confidece interval 95%

d

0,05

0,10

0,15

0,20

0,25

0,30

0,35

0,40

0,45

0,50

0,05

73

138

196

246

288

323

350

369

380

384

0,10

18

35

49

61

72

81

87

92

95

96

2.4. Study techniques

-Clinical evaluation and Hackett classification of spleenomegaly;

-Body temperature, body weight taking, nutrition condition evaluation;

-Urine analysis for cheking antimalarial components;

-Microscopic slide checking and parasite counting;

-Molecular markers analysis and genotyping of malaria parasites

-Measure of chloroquine and desethylchloroquine.

2.5. Clinical and laboratory assessment procedures

Studies of directly observed treatment for uncomplicated malaria are prospective evaluations of clinical and parasitological responses o­n days 0, 1, 2, 3, 7, 14, 21 and 28 (with CQ) and 35, 42 (with DHA-PPQ). The day the patient is enrolled and receives the first dose of medicine is day 0.

Timing for follow up

D0

D1

D2

D3-6

D7

D14

D21

D28

D35

D42

Other day

Standard procedures

 

 

 

 

 

 

 

 

 

 

 

1. Clinical evaluation

x

x

x

x

x

x

x

x

x

x

(x)

2. Body temperature

x

x

x

x

x

x

x

x

x

x

(x)

3. Slide checking

x

x

x

x

x

x

x

x

x

x

(x)

4. Urine test

x

 

 

 

 

 

 

 

 

 

 

5. Blood analysis:

- Haemoglobin

- Haematocrite

- PCR

 

x

x

x

 

 

 

 

 

 

x

 

 

 

x

 

 

 

x

 

 

 

x

 

 

 

x

 

 

 

x

 

 

 

(x)

6. Parasite genotyping

x

 

 

x

x

x

x

x

x

x

(x)

7. Drug analysis

x

 

 

 

x

 

 

x

 

 

Post D7

Patients treatment

 

 

 

 

 

 

 

 

 

 

 

1. DHA-PPQ

x

x

x

 

 

 

 

 

 

 

 

2. Chloroquine

x

x

x

 

 

 

 

 

 

 

 

2. Rescue drugs

 

(x)

(x)

(x)

(x)

(x)

(x)

(x)

(x)

(x)

(x)

2.6. Loss to follow up

-Loss to follow up occurs when despite all reasonable efforts, an enrolled patient does not attend the scheduled visits;

-Patients who are lost to follow up but who subsequently return to the study site before day 28/42 will not be turned away and will be encouraged to return for check up visits.

2.7. Patient discontinuation or protocol violation

-Study patients who meet any of the following criteria will be classified as withdrawn:

+Withdrawal of consent of a patient at any time;

+Failure to complete treatment, due to persistent vomiting of the treatment, or failure to attend the scheduled visits during the first 3 days or serious adverse events necessitating termination of treatment before the full course is completed.

-Enrolment violation: severe malaria o­n D0 or voluntary protocol violation or involuntary protocol violation occurrence during follow-up of concomitant disease, or detection of mono-infection with another malaria species during follow-up.

2.8. Classification of responses to treatment outcomes (WHO, 2009)

The classification of drug response in line with World Health Organization guidelines, included of Early Treatment Failure (ETF), Late Clinical Failure (LCF), Late Parasitological Failure (LPF), and Adequate Clinical and Parasitological Response (ACPR).

2.9. Adverse events and safety profiles

-An adverse event (AE): any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment, that occurs during the course of the study;

-Serious AE as any untoward medical occurrence that results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability.

2.10. Data analysis and study end-points

-Data in patient were entered o­n WHO-Ringwald Pascal software version 7.1. Results should be expressed as the proportion of ACPR (or proportion of ETF, LPF or LCF) before and after adjustment by PCR;

-Parasite clearance time (PCT), fever clearance time (FCT), and the proportion of patients who are parasitemic o­n day 3.

2.11. Ethical issues in clinical trials

-Approval by the official ethical and scientific committee. Study team members must be passed GCPs and do as SOPs in protocol;

-Informed consent when patients will be included in the study;

-Confidentiality: all information o­n patients will remain confidential;

-Health-care services: free health care throughout follow-up for any illness related to malaria will be provided to the study patients regardless of treatment outcome.

3. RESULTS AND DISCUSSIONS

3.1. DHA-PPQ efficacy in the treatment of falciparum malaria

Table 3.1. Baseline clinical characteristics of patients at D0

Study patient?s profile

(N = 206)

At the point start of study D0

Quang Tri

(n = 76)

Gia Lai

(n = 65 )

Ninh Thuan

(n = 65)

Temperature & body weight

Mean temperature in 0C

Mean weight in kg

Fever day number before test

 

38.22 1.04

41.5 12.8

2.2 1.6

 

37.78 1.2

39.5 15.1

2.6 1.1

 

38.16 1.0

40.5 14.2

2.2 1.2

Fever or history of fever

Body temperature ? 37.50C

History of fever(past 48 hours)

Non fever & non-history of fever

 

62 (81.58)

8 (10.53)

6 (7.89)

 

58 (89.23)

7 (10.77)

0

 

45 (69.23)

12 (18.46)

8 (12.31)

Spleen status

Enlarged spleen

Non-spleenomegaly

History of splenectomy

 

42 (55.26)

34 (44.74)

0

 

8 (12.31)

55 (84.62)

2 (3.07)

 

46 (70.77)

19 (29.23)

0

The mean temperature at D0 were 38.22 1.040C, 37.78 1.20C, and 38.16 1.00C in sentinel site of Quang tri, Gia Lai, and Ninh Thuan, respectively. Number fever days of patients at D0 was around 1-4 days. Number of cases of enlarged spleen were 55.26%, 12.31% and 70.77% respectively in Quang Tri, Gia Lai and Ninh Thuan. These suitable for most of patients were living in hyperendemic malaria areas, hence they often get malaria and many ?reinfection attack? lead to spleen parenchyma hypertrophy and fibrosis. Especially, in this trial, 2 cases with abnormal spleen status (one case of congenital hyposplenism syndrome and o­ne of totally splenectomy due to accident.

Table 3.2. Laboratory findings and malaria parasite profile in patients

Patients? parameters

Quang Tri

Gia Lai

Ninh Thuan

Median parasite density

- Asexual parasite/ ml

 

- Positive gametocyte cases

 

28.125

(12.121 - 49.862)

9 (11.84%)

 

33.197

(16.520 - 76.268)

11 (16.92%)

 

30.192

(18.415 - 52.202)

4 (6.15%)

Haematology parameters

- Mean haemoglobine

 

- Mean haematocrite

 

9.9 (g/dL)

(7.9 ? 17.4)

40.12%

(37.25 ? 41.71)

 

11.8 (g/dL)

(9.2 ? 14.6)

39.58%

(41.42 ? 44.02)

 

11.3 (g/dL)

(7.1 ? 14.8)

41.17%

(36.80 ? 45.82)

The median malaria parasite density of asexual P. falciparum at three sentinel sites around 28.125-33.197/ml. Number of cases with positive gametocyte were low (6.15-16.92%) in Quang Tri, Gia Lai, and Ninh Thuan, respectively.

B?ng 3.3. Efficacy of DHA-PPQ vs. uncomplicated falciparum malaria

Treatment outcomes

Quang Tri

Gia Lai

Ninh Thuan

n

%

n

%

n

%

ETF

0

0

2

3.71

0

0

LCF

0

0

3

4.62

0

0

LPF

0

0

0

0

0

0

ACPR

69

100

55

91.67

46

100

Total of analysis

69

 

60

 

46

 

Withdraw

2

2.63

0

0

2

3.08

Loss of follow (post D7)

5

6.58

5

7.69

17

26.15

Total of study

76

 

65

 

65

 

Followed up to the day 42 in vivo guidelines from WHO, efficacy analysis at each sentinel site showed that in Quang Tri and Ninh Thuan with ACPR or cure rate of 100%, but in Gia Lai sentinel site with ACPR at D42 only 91.67%, accompanied with ETF of 3.71%, LCF of 4.62%. In 2 cases of ETF, the case of 05GLAK with high parasite density at D0 (99.857/ml), therefore till prolong to the day D5 this case was completely parasite clearance. And the case of 65GLAK with parasite density of 49.673/ml, but till positive asexual P. falciparum forms after 3 days regimen and high body temperature. Both of cases are normal spleen parenchyma as above mentioned. Regarding to role of the spleen, when patients are infected with malaria, intra-erythrocytic parasite development results in remodeling of both infected and non-infected red blood cells (RBCs). The spleen filters these altered RBCs. This suggested that this splenic-pitting is responsible for a majority of the parasite clearance that is seen in patients. In fact, asplenic individuals living in falciparum endemic regions, exhibit more frequent fevers, higher parasitemias, and longer parasite clearance times following treatment with antimalarials such as artemisinin. Studies using P. berghei-infected mice, found that animals with full splenectomies had parasitemias double those found in intact and partially splenectomized mice. In other study in experiment animal, when assessed parasite clearance in DHA-treated intact and asplenic mice, it was found that the capacity to clear parasites was reduced in the asplenic population.

Table 3.4. Analysis of early treatment failure cases by in vivo test

Study?s code

Parasite density

D appear

Classified by in vivo

Do

D appear

05GLAK

99.857

141 (P.f)

D3

ETF (+ prolong D4)

65GLAK

49.673

36 (P.f)

D3

ETF (? 38.00C)

29GLAK

45.245

108 (P.f)

D42

LCF

48GLAK

11.544

72 (P.f)

D42

LCF

62GLAK

40.320

81.030 (P.f)

D26

LCF

In two cases of ETF, the case of 05GLAK with extremely high parasite density at D0 (99.857/ml), therefore till prolong to the day D5, and the case of 65GLAK with parasite density of 49.673/ml, but till positive asexual P. falciparum forms after 3 days. The cases of LCF at the D26 or D42 must be done in PCR analysis.

Table 3.5. Discrimination of reinfection or recrudescence by PCR

Study?s code

Parasite density

Classified

by in vivo

Classified

by PCR adjusted

Do

Dfailure

GLAK29

45.245

108 (P.f)

LCF (D42)

Reinfection

GLAK48

11.544

72 (P.f)

LCF (D42)

Reinfection

GLAK62

40.320

81.030 (P.f)

LCF (D26)

Recrudesence

The result of adjusted-PCR showed that 2 cases of LCF were reinfection or new infection of P. falciparum (29GLAK and 48GLAK) at the day D42. Specially, the case of 62GLAK was recrudescence o­n the D26. This patient has parasite cleared after 3 days treatment of DHA-PPQ, then reappeared of P. falciparum alone at D26. With the results of LCF in Gia Lai sentinel, after corrected-PCR, efficacy was changed increasing the ACPR rate from 91.67% to 95%, the LCF rate reducing from 4.62% to 1.29%, two cases of reinfection or new infection, and the rest 2 cases of ETF were 3.71%.

Table 3.6. PCR-adjusted and unadjusted treatment outcomes

 

Treatment outcomes

Before PCR-adjusted

After PCR-adjusted

n

%

n

%

ETF

2

3.71

2

3.71

LCF

3

4.62

1

1.29

LPF

0

0

0

0

ACPR

55

91.67

57

95.0

Total of analysis

60

 

60

 

Withdraw

0

0

0

 

Loss to follow up

5

7.69

5

7.69

Total of study

65

 

65

 



Figure 3.1. Efficacy of DHA-PPQ versus P. falciparum at 3 sentinel sites

With the results PCR corrected in discrimination of recrudescence and reinfection, DHA-PPQ efficacy was changed increasing the ACPR rate from 91.67% to 95%, the LCF rate reducing from 4.62% to 1.29%.

Table 3.7. Efficacy of DHA-PPQ in parasite and fever clearance

Analysis parameters

Quang Tri

Gia Lai

Ninh Thuan

Parasite density/ml at D0

28.125

(12.121-49.862)

32.197

(16.520-76.268)

30.192

(18.415-52.202)

Parasite clearance time (PCT)

37.8h

(35.6-39.8)

61.5h

(36.2-79.6)

37.3h

(34.6-38.6)

Body temperature at D0

37.3

(36.0-40.1)

38,1

(36.2-40.5)

37.3

(35.6-39.4)

Fever clearance time (FCT)

25.7h

(24.7-26.7)

30.7h

(29.0-32.4)

27.3h

(25.4-29.2)

The differences in the baseline median parasite density between the treatment groups are not significant at the day D0. However, compared to Quang Tri and Ninh Thuan, Gia Lai sentinel showed that parasite clearance time (61.5h) much longer than Quang Tri (37.8h) and 37.3h (Ninh Thuan). In paralell with rapid PCT, the clinical symptomes would be improved better at Quang Tri and Ninh Thuan, but in Gia Lai seemed to be longer in fever clearance time as some patients who are positive asexual parasite at 72 hours or more.

Table 3.8. Proportion of positive asexual P. falciparum at  D3

Results in sentinel sites

Proportion of parasitaemic o­n D3

Quang Tri

Gia Lai

Ninh Thuan

Cases with positive at D3

0

10 (15.38)

0

Cases with positive at post-D3

0

1 (1.62)

0

Total

0

11 (17.0)

0

Analysis of all cases of asexual parasite existence, the positivity rate of 17% at day 3 (72 hours) after treatment with DHA-PPQ in Gia Lai as an important indirect clinical indicator of treatment failure or resistance.

Table 3.9. Progression and asexual parasite clearance from D0 to D3

 

Patients? code

Age

D0

D1

D2

D3

D4

D5

1

GLAK05

29

99.857

36.666

4.890

282

80

0

2

GLAK14

32

48.875

2.130

165

48

0

0

3

GLAK 15

30

75.559

16.395

360

6

0

0

4

GLAK23

28

46.941

29.480

102

537

0

0

5

GLAK27

15

56.303

6.225

66

12

0

0

6

GLAK44

33

43.385

17.139

1.875

66

0

0

7

GLAK46

13

29.919

17.213

1.695

162

0

0

8

GLAK60

14

16.493

1.155

54

24

0

0

9

GLAK61

31

31.014

11.333

756

267

0

0

10

GLAK62

4

40.320

6.120

201

150

Recrudescence

11

GLAK65

5

49.673

12.300

483

36

0

0

Mean parasite density D0/mL

44.121

9.633

358

66

8

0



Figure 3.2. Progression of parasite clearance day by day (24h)

In total of 65 cases in Gia Lai sentinel site, there was 17% rate of positive parasite at day D3 or D4.This mean parasite clearance data by step every 24h from D0 to D5 in detail of 44.121/mL decreased by 9.633/mL, 358/mL, 66/mL, 8/mL, and 0/mL, respectively. This is currently the best available indicator here, need to be more analysis of pharmacokinetics.

Analysis of all cases of asexual parasite existence, the positivity rate of 17% at day 3 (72 hours) after treatment by DHA-PPQ regimen in Gia Lai as an important indirect clinical indicator of treatment failure or resistance, and the parasitemic o­n day 3 is currently the best available indicator used in routine monitoring to measure P. falciparum sensitivity to artemisinins. With an increase in parasite clearance time (61.5h) and evidence 17% of cases with parasites detectable o­n day 3 after treatment with DHA-PPQ. To make sure exact resistance, need to be done more pharmacokinetic and molecular marker analysis in the next time.

Table 3.10.Proportions of adverse events in DHA-PPQ treated group

DHA-PPQ

Quang Tri

Gia Lai

Ninh Thuan

Time at occurrence

On drug tolerability

n (%)

n (%)

n (%)

 

Diarrhea

0

0

0

 

Vomit after oral taken*

2 (2.63)

0

1 (1.54)

D0 - D1

*Temperature at vomitting

? 37,5 - < 390C

? 39.00C

 

0

2 (2.63)

 

0

0

 

0

1 (1.54)

 

Adverse events

n (%)

n (%)

n (%)

 

Headache

6 (7.89)

3 (4.62)

4 (6.16)

D0 - D3

Dizziness

2 (2.63)

2 (3.08)

3 (4.62)

D0 - D2

Nausea

3 (3.95)

2 (3.08)

2 (3.08)

D0 - D1

Loss of appetite

4 (5.26)

2 (3.08)

3 (4.62)

D0 - D3

Mild abdomen pain

1 (1.32)

0

1 (1.54)

D0 - D2

Mouth dry

0

1 (1.54)

0

D0 - D3

Icth, urticaria

1 (1.32)

2 (3.08)

0

D0 - D3

Sleep troubles

1 (1.32)

2 (3.08)

0

D0 - D3

Using consecutive 3 days of DHA-PPQ therapy, some adverse events were observed. Several other mild side-effects including headache, dizziness, nausea, itching and rash. It is very difficult to differentiate these adverse events with malaria disease symptoms.

3.2. Chloroquin efficacy in the treatment of vivax malaria patients

Table 3.11. Baseline clinical characteristics of patients before trials

Patients? profile

Quang Tri

(n = 56)

Gia Lai

(n = 62 )

Ninh Thuan

(n = 47)

Body temperature & weight

Mean body temperature (0C)

Mean weight in kg

Fever day number before test

 

38.51 1.15

42.8 14.6

2.1 1.1

 

38.29 1.20

36.5 18.2

3.1 1.1

 

38.29 1.20

39.5 15.2

3.2 1.4

Fever or history of fever

Fever ? 37,50C

History of fever (past 48h)

 

47 (83.93)

9 (16.07)

 

39 (62.90)

23 (37.10)

 

38 (80.6)

9 (8.96)

Enlarged spleen status

I + II grade

III grade

19 (33.93)

17 (30.36)

2 (3.57)

16 (25.81)

12 (19.35)

4 (6.46)

27 (40.30)

24 (35.82)

3 (4.48)

Some baseline clinical and paraclinical characteristics of patient profile showed that most of patients were fever or history of fever during past 48hs before study enrollment, and mean body temperature at 3 sentinel sites around 38.51 1.150C; 38.29 1.20C and 38.29 1.200C in Quang Tri, Gia Lai and Ninh Thuan, respectively. Because of living in hyperendemic malaria areas, the patients had enlarged spleen of 33.93%; 25.81% and 40.30% in Quang Tri, Gia Lai, and Ninh Thuan, respectively. Majority in spleenomegaly cases, grade I and II.

Table 3.12. The haematology and malaria parasite profile in patients

Patient?s profile

At the point start of study D0

Quang Tri

Gia Lai

Ninh Thuan

Median parasite density

- Asexual parasite/ml

 

- Positive gametocyte cases

- Gametocyte density/ml

 

3.185

(748-52.154)

42 (75.0%)

102.7

(66.3-139)

 

3.256

(200-33.121)

50 (80.65%)

101.5

(67.3-128)

 

2.810

(250-37.750)

42 (89.36%)

108.4

(62.2-130)

Haematology parameter

- Haemoglobine (g/dL)

 

- Haematocrite (%)

 

9.3

(7.4-15.6)

39.34

(36.21-42.72)

 

11.5

(9.4-14.2)

39.51

(40.41-42.12)

 

10.5

(8.2-15.4)

41.2

(37.9-44.85)

Median asexual form of P. vivax parasite were 3.185; 3.256 and 2.810/ml in Quang Tri, Gia Lai, and Ninh Thuan sentinel sites, respectively. Especially, number of vivax malaria cases had positive gametocyte of 75%, 80.65% and 89.36%.

Table 3.13. The efficacy of CQ regimen vs. P. vivax malaria

Treatment outcomes

Quang Tri

Gia Lai

Ninh Thuan

n

%

n

%

n

%

ETF, LCF, LPF

0

0

0

0

0

0

ACPR

54

100

52

100

44

100

Total of analysis

54

 

52

 

44

 

Withdraw

0

0

2

3.23

0

0

Loss to follow up

2

3.57

8

12.90

3

6.38

Total of study

56

 

62

 

47

 



Figure 3.3. Efficacy of CQ regimen vs. P. vivax malaria

The data showed that the ACPR were 100% in three sentinel sites.

Table 3.14. Efficacy in parasite clearance and fever clearance of CQ

Analysis parameters

Quang Tri

Gia Lai

Ninh Thuan

Median parasite density/ml at D0

3.185

(748-52.154)

3.256

(210-33.121)

2.810

(250-37.750)

Mean parasite clearance time (PCT)

39.267.68

31.22 6.28

41.2 4.69

Mean temperature at D0

38.5 1.5

37.5 1.7

38.5 1.0

Mean fever clearance

time (FCT)

28.14 10.16

25.16 12.17

29.20 13.2

Concerning parasite and fever clearance time, after 3 days of CQ therapy, PCT were 39.26 7.68h; 31.22 6.28h and 41.20 4.69 h in sentinel of Quang Tri, Gia Lai and Ninh Thu?n, respectively. Although mean body temperature of patients were 38.5 1.50C, 37.5 1.70C and 38.5 1.00C, the FCT were about 48 hours. These does mean stable CQ-sensitive P. vivax.

However, with the literature of drug resistance all over the world, especially in the neighboring countries of the Mekong subregion, and with the fact that CQ has been used for over 60 years with various purposes, the warning signs of reduced susceptibility or resistance may occur in Vietnam and Central-Western highlands in particular in the near future. Routine supervisions of the drug efficacy in some areas, especially in endemic areas with higher proportion of P. vivax of the parasite formula, is really necessary.

Table 3.15. Proportions of adverse events in CQ treated group

Symptoms

Quang Tri

Gia Lai

Ninh Thuan

Time

Headache, dizziness

0

2 (3.22)

1 (2.13)

D1- D3

Nausea

1 (1.79)

2 (3.22)

2 (4.26)

D0 - D2

Abdomen pain

2 (3.58)

0

0

D1 - D2

Itch, urticaria, rash

1 (1.79)

1 (1.61)

1 (2.13)

D0 - D2

Vision blurred

0

2(3.22)

0

D1 ? D3

Due to difficulties in recording the symptoms reported or exclusively relating to P. vivax infection, these studies showed that some mild and low proportion adverse events by every 12 hours interval examination in first 3 consecutive days, such as nausea, abdomen pain, itching, headache, dizziness, rash, or vision blurred.

CONCLUSIONS AND RECOMMENDATIONS

1. Conclusions

1.1. The efficacy of DHA-PPQ regimen to P. falciparum malaria

-Adequate clinical and parasitological responses (ACPR) in 3 sentinel sites were from 95-100%, including 100% of absolute cure rate in Quang Tri, Ninh Thuan; except for Gia Lai sentinel with the ACPR after corrected-PCR of 95%, LCF of 1.29% and ETF of 3.71%;

-PCT and progression was very quick, within 48 hours o­nly; except for some cases in Gia Lai was positive asexual parasite in day 3 or ? 72 hours. FCT in parallel with PCT was just within 48 hours in Quang Tri & Ninh Thuan, but longer in Gia Lai;

-The proportion of positive D3 of 17% as clinical marker for suspected resistance.

1.2. The drug efficacy of chloroquine in treatment of P. vivax malaria

-The efficacy CQ was still maintains at absolutely high level to P. vivax malaria patients, and the ACPR were 100% in 3 sentinel sites;

-The chloroquin?s PCT and FCT as well were quick, within 48 hours since CQ was given;

-Generally, good tolerance of DHA-PPQ and CQ was found in the treatment of uncomplicated P. falciparum and P. vivax malaria patients. Some side-effects occurred at mild level, with low proportion, no serious reactions that require no interventions with first aid or drug withdrawals, especially these symptoms have improved remarkably after drug withdrawals.

2. Recommendations

At present, the combined DHA-PPQ regimen is highly efficacious; however, the weakness include LCF (1.29%) and ETF (3.71%) in 2 patients with abnormal spleens, and high rate of parasite existence in D3 day (17%) in DHA-PPQ regimen as an indicator of drug resistance. Therefore, it is recommended that:

-The role of the spleen is very obvious in parasite clearing intervention, so that it is necessary to supplement this criterion into ?exclusive criteria? of the proposals to assess the P. falciparum and P. vivax drug efficacy in vivo when conducting the research in the field or evaluating the effectiveness at the hospital treatment system;

-All the cases with parasite existence until D3 after completing DHA-PPQ therapy, there should be more analyses of pharmacokinetics aspect, molecular markers to confirm the susceptibility/ resistance of P. falciparum in the treatment with DHA-PPQ more thoroughly;

-The CQ regimen as recommended by the MoH still remains effective; therefore, CQ is considered the first of choice for P. vivax malaria treatment, but need to monitoring of their efficacy routinely.

References


 


 

06/05/2018
Dr. Huynh Hong Quang et al.,
Institute of Malariology, Parasitology, and Entomology Quy Nhon,
 
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