Background
Methods
Data pooling
Ethical approval
Dosing calculation
Classification of study sites in transmission zones
Statistical analysis
Results
Characteristics of included studies
Study
a
|
Number of patients treated with AS-AQ
|
Country
|
Age range (months)
|
Target dose (mg/kg) for artesunate & amodiaquine
|
Manufacturer
|
Formulation
|
Supervision
|
Reference
|
---|---|---|---|---|---|---|---|---|
Adjuik-2002
| 390 | Multicentric | 6-59 | 12 & 30 | Sanofi-Synthélabo & Parke-Davis | Loose NFDC | Full | [8] |
Anvikar-2012
b
| 199 | India | 6-720 | 12 & 30 | Sanofi-Aventis | FDC | Full | [36] |
Barennes-2004
| 32 | Burkina Faso | 12-180 | 12 & 30 | Sanofi Winthrop AMO & Hoechst Marion Roussel | Loose NFDC | Full | [64] |
Bonnet-2007
| 110 | Guinea | 6-59 | 12 & 30 | Guilin Pharmaceutical & Parke-Davis | Loose NFDC | Full | [65] |
Brasseur-2009
b
| 276 | Senegal | All ages | N/A | Sanofi-Aventis | Co-blistered NFDC | Full/partiale | [17] |
Bukirwa-2006
| 203 | Uganda | 12-120 | 12 & 25 | Sanofi-Aventis & Parke-Davis, Pfizer | Loose NFDC | Full | [66] |
Dorsey-2007
| 145 | Uganda | 12-120 | 12 & 25 | Sanofi-Aventis & Pfizer | Loose NFDC | Full | [67] |
Espié-2012
| 149 | DRC | 6-59 | 12 & 30 | Sanofi-Aventis | FDC | Full | [34] |
Faucher-2009
| 94 | Benin | 6-60 | 12 & 30 | Sanofi-Aventis | FDC | Partial | [68] |
Faye-2010
| 155 | Multicentric | >84 | N/A | Pfizer | Co-blistered NFDC | Full | [69] |
Gaye-2010b
d
| 129 | Senegal | 12-720 | 12 & 30 | Sanofi-Aventis | FDC | Full | [Unpublished] |
Grandesso-2003
d
| 86 | Uganda | 6-59 | 12 & 30 | Sanofi & Park-Davis | Loose NFDC | Full | [Unpublished] |
Grandesso-2006
| 123 | Sierra Leone | 6-59 | 12 & 30 | Sanofi Winthrop AMO & Pfizer | Loose NFDC | Full | [44] |
Guthmann-2005
| 96 | Angola | 6-59 | 12 & 30 | Sanofi Winthrop & Parke Davis | Loose NFDC | Full | [70] |
Guthmann-2006
| 68 | Angola | 6-59 | 12 & 30 | Sanofi Winthrop & Parke Davis | Loose NFDC | Full | [71] |
Hamour-2005
| 71 | Sudan | 6-59 | 12 & 30 | Sanofi & Park-Davis | Loose NFDC | Full | [72] |
Hasugian-2007
| 93 | Indonesia | >12 | 12 & 30 | Guilin Pharmaceuticals & Aventis | Loose NFDC | Full | [6] |
Jullien-2010
| 27 | Kenya | 216-720 | N/A | Sanofi-Aventis | Co-blistered NFDC | Full | [73] |
Jullien-2010
| 24 | Kenya | 216-720 | 12 & 30 | Sanofi-Aventis | FDC | Full | [73] |
Juma-2005
d
| 201 | Kenya | 6-59 | 12 & 30 | Sanofi-Aventis | Loose NFDC | Full | [Unpublished] |
Karema-2006
| 251 | Rwanda | 12-59 | 12 & 30 | Sanofi-Aventis | Loose NFDC | Full | [74] |
Kayentao-2009
| 128 | Mali | 6-59 | 12 & 30 | - | Co-blistered NFDC | Full | [75] |
Laminou-2011
d
| 80 | Niger | 6-180 | 12 & 30 | Sanofi-Aventis | FDC | Partial | [Unpublished] |
Mårtensson-2005
| 202 | Tanzania | 6-59 | 12 & 30 | Mepha & Roussel | Loose NFDC | Full | [45] |
Menan-2012
d
| 110 | Ivory Coast | 12-480 | 12 & 30 | Sanofi-Aventis | FDC | Full | [Unpublished] |
Menard-2008
| 332 | Madagascar | 6-180 | 12 & 30 | - | Loose NFDC | Full | [76] |
Ndiaye-2009
| 625 | Multicentric | All ages | 12 & 30 | Sanofi-Aventis | FDC | Full | [30] |
Ndiaye-2011
| 179 | Senegal | All ages | 12 & 30 | Sanofi-Aventis | FDC | Fullf | [32] |
Nikiema-2010
d
| 527 | Burkina Faso | 6-120 | 12 & 30 | Sanofi-Aventis | FDC | Full | [Unpublished] |
Osorio-2007
| 37 | Columbia | 12-780 | 12 & 30 | Sanofi-Aventis | Loose NFDC | Full | [77] |
Rwagacondo-2004
| 157 | Rwanda | 6-59 | 12 & 30 | Dafra | Loose NFDC | Full | [11] |
Sagara-2012
| 230 | Mali | ≥6 | 12 & 30 | Sanofi-Aventis | Co-blistered NFDC | Full | [78] |
Sanofi-2013
d
| 203 | Uganda | 6-59 | 12 & 30 | Sanofi-Aventis | FDC | Fullf | [Unpublished] |
Schramm-2013
| 147 | Liberia | 6-72 | 12 & 30 | Sanofi-Aventis | FDC | Full | [38] |
Sinou-2009
c
| 13 | Congo | ≥192 | 12 & 30 | Saokim Pharmaceuticals Co | FDC | Full | [31] |
Sirima-2009
b
| 441 | Burkina Faso | 6-59 | 12 & 30 | Sanofi-Aventis | Co-blistered NFDC | Full | [18] |
Sirima-2009
b
| 437 | Burkina Faso | 6-59 | 12 & 30 | Sanofi-Aventis | FDC | Full | [18] |
Smithuis-2010
| 142 | Myanmar | >6 | 12 & 32/4 | Sanofi-Aventis | FDC | Partial | [7] |
Staedke-2004
| 130 | Uganda | 6-120 | 12 & 25 | Sanofi-Pfizer | Loose NFDC | Full | [79] |
Swarthout-2006
| 82 | DRC | 6-59 | 12 & 30 | Sanofi and Parke Davis & Pfizer | Loose NFDC | Full | [80] |
Temu-2010
d
| 99 | Liberia | 6-60 | 12 & 30 | Sanofi-Aventis | FDC | Full | [Unpublished] |
The 4ABC StudyGroup-2011
| 981 | Multicentric | 6-59 | 12 & 30 | Sanofi-Aventis | FDC | Full | [15] |
Thwing-2009
| 101 | Kenya | 6-59 | 12 & 25 | Cosmo Pharmaceuticals & Pfizer | Loose NFDC | Full | [46] |
van den Broek-2006
| 87 | Congo | 6-59 | 12 & 30 | Cosmo Pharmaceuticals & Pfizer | Loose NFDC | Full | [81] |
Yeka-2005
| 714 | Uganda | ≥6 | 12 & 25 | Sanofi-Pfizer | Loose NFDC | Full | [82] |
Drug formulations
Formulation
|
Tablet strength
| |||
---|---|---|---|---|
Pediatric formulation
|
Adult formulation
| |||
AQ
|
AS
|
AQ
|
AS
| |
Loose NFDC
| - | - | 200 mg | 50 mg |
Co-blistered NFDC
| - | - | 153 mg | 50 mg |
FDC (Trimalact®)
| - | - | 300 mg | 100 mg |
FDC (Coarsucam®/Winthrop®)
| 67.5 mg | 25 mg | 270 mg | 100 mg |
135 mg | 50 mg |
Baseline characteristics
Variable
|
Asia
|
Africa
|
South America
a
|
Overall
|
---|---|---|---|---|
N | 434 (4.77%) | 8635 (94.83%) | 37 (0.41%) | 9106 |
Study period | 2005-2009 | 1999-2012 | 2000-2004 | 1999-2012 |
Gender
| ||||
Female | 38.7% [168/434] | 47.0% [4,060/8,635] | 18.9% [7/37] | 46.5% [4,235/9,106] |
Age
| ||||
Median age [IQR, range] in years | 17 [8-28,0.6-80] | 3 [1.7-5,0-80] | 20 [16-25,8-58] | 3 [1.8-6, 0-80] |
<1 y | 0.2% [1/434] | 9.1% [782/8,635] | 0.0% [0/37] | 8.6% [783/9,106] |
1 to <5 y | 7.8% [34/434] | 65.1% [5,619/8,635] | 0% [0/37] | 62.1% [5,653/9,106] |
5 to <12 y | 25.3% [110/434] | 16.5% [1,421/8,635] | 10.8% [4/37] | 16.9% [1,535/9,106] |
≥12 y | 66.6% [289/434] | 9.4% [813/8,635] | 89.2% [33/37] | 12.5% [1,135/9,106] |
Treatment supervision
b
| ||||
Full | 67.3% [292/434] | 95.1% [8,212/8,635] | 100.0% [37/37] | 93.8% [8,541/9,106] |
Partial | 32.7% [142/434] | 4.9% [423/8,635] | 0.0% [0/37] | 6.2% [565/9,106] |
Drug formulation
| ||||
Fixed dose combination (FDC) | 78.6% [341/434] | 44.0% [3,797/8,635] | 0.0% [0/37] | 45.4% [4,138/9,106] |
Co-blistered non-fixed dose combination (co-blistered NFDC) | 0.0% [0/434] | 14.6% [1,257/8,635] | 0.0% [0/37] | 13.8% [1,257/9,106] |
Loose non-fixed dose combination: target dose 25 mg/kg (loose NFDC-25) | 0.0% [0/434] | 15.0% [1,293/8,635] | 0.0% [0/37] | 14.2% [1,293/9,106] |
Loose non-fixed dose combination: target dose 30 mg/kg (loose NFDC-30) | 21.4% [93/434] | 26.5% [2,288/8,635] | 100.0% [37/37] | 26.6% [2,418/9,106] |
Enrolment clinical variables
| ||||
Geometric mean parasitemia [95% CI] in parasites/μl | 8,504 [7,409-9,761] | 19,508 [18,944-20,089] | 80 [55-116] | 18,338 [17,801-18,891] |
Median weight [IQR, range] in kg | 40 [20-50,7-72] | 12 [10-17, 5-104] | 59 [47-65,24-80] | 12.7 [10-18, 5-104] |
Underweight for agec | 37.1% [13/35] | 20.6% [1,248/5,821] | - | 20.7% [1,297/6,269] |
Anemic (hb < 10 g/dl)d | 34.3% [149/434] | 59% [3,754/5,821] | 13.5% [5/37] | 56.6% [3,908/6,906] |
Gametocytes presencee | 39.4% [56/142] | 10.0% [462/5,821] | 24.3% [9/37] | 11.0% [527/4,796] |
Fever (temp > 37.5 °C) | 77.7% [227/292] | 66.4% [5,769/5,821] | 16.2% [6/37] | 68.5% [6,002/8,766] |
Hemoglobin [mean ± SD] in g/dl | 10.9 ± 2.29 | 9.5 ± 2.06 | 12.06 ± 1.93 | 9.6 ± 2.11 |
Distribution of AQ and AS dosing
FDC
|
Co-blistered NFDC
|
Loose NFDC-30
|
Loose NFDC-25
| |
---|---|---|---|---|
Artesunate dose (mg/kg)
a
| ||||
<1 y | 10.7 [9.4-12.5 , 7.5-16.7] | 10.7 [9.6-12.3 , 7.5-20.5] | 12.5 [10.6-13.7 , 8.3-17.9] | 12.5 [10.7-14.1 , 9.5-15] |
1 to <5 y | 12.5 [10.7-15 , 5.4-30] | 13.4 [11.2-15.2 , 4.8-30] | 12.6 [11.5-13.6 , 6.8-30] | 12.5 [11.3-13.4 , 10.4-14.1] |
5 to <12 y | 12.5 [10-15 , 7-20] | 11.5 [9.7-13.7 , 5.5-21.4] | 11.5 [10-12.5 , 6.8-15] | 12.5 [11.9-13 , 11.5-13.4] |
≥12 y | 10.9 [9.5-13 , 5.8-21.4] | 10.9 [9.4-13 , 6-24] | 11.5 [10.9-12.1 , 7.5-14] | 11.7 [11.2-12 , 7.8-12.5] |
Overall | 12 [10-14.5 , 5.4-30] | 12.0 [10-15 , 4.8-30] | 12.5 [11.1-13.5 , 6.8-30] | 12.5 [11.5-13.1 , 7.8-15] |
Amodiaquine dose (mg/kg)
a
| ||||
<1 yb | 28.9 [25.3-33.8 , 20.3-45] | 32.6 [28.7-36.5 , 22.8-62.9] | 33.9 [30.3-37 , 19-50] | 22.9 [21.4-25 , 19-30] |
1 to <5 y | 33.8 [28.9-40.5 , 14.5-81] | 38.3 [32.2-45.9 , 14.8-91.8] | 33.3 [30-37.5 , 19.7-60] | 25.0 [22.7-25 , 21.1-25] |
5 to <12 y | 33.8 [27-40.5 , 18.9-54] | 35.3 [29.5-42 , 16.7-65.6] | 34.1 [31.6-39.8 , 27.3-60] | 24.1 [23.7-25 , 22.6-26] |
≥12 y | 29.5 [25.7-35.2 , 15.6-57.9] | 33.4 [28.7-39.9 , 18-73.4] | 38.9 [33.3-44.2 , 28.1-55.8] | 24.0 [23.1-25 , 15.6-26] |
Overall | 32.4 [27-39 , 14.5-81] | 35.3 [30.6-43.7 , 14.8-91.8] | 33.7 [30.6-38.1 , 19-60] | 25.0 [22.7-25 , 15.6-30] |
Early parasitological response
Late parasitological response
Survival estimates on day 28
a, b
|
Survival estimates on day 42
a, b
| |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
FDC
|
Co-blistered NFDC
c
|
Loose NFDC-30
|
Loose NFDC-25
c
|
FDC
|
Loose NFDC-30
| |||||||
Age category
|
At risk
|
K-M [95% CI]
|
At risk
|
K-M [95% CI]
|
At risk
|
K-M [95% CI]
|
At risk
|
K-M [95% CI]
|
At risk
|
K-M [95% CI]
|
At risk
|
K-M [95% CI]
|
<1 y | 207 | 97.8 [95.9-99.7] | 77 | 98.7 [96.3-100] | 222 | 93.8 [90.7-96.8] | 95 | 90.9 [85.6-96.1] | 42 | 95.6 [90.9-100] | 28 | 85.7 [76.6-94.9] |
1 to <5 y | 2,044 | 97.9 [97.3-98.5] | 511 | 96.9 [95.4-98.3] | 1,340 | 94 [92.8-95.2] | 532 | 92.2 [90.2-94.2] | 325 | 95.7 [94-97.3] | 103 | 92.5 [90-94.9] |
5 to <12 y | 565 | 98.1 [97-99.2] | 192 | 98.6 [97-100] | 317 | 98.8 [97.5-100] | 211 | 97.4 [95.3-99.5] | 65 | 95.4 [91.6-99.2] | 15 | 98.8 [97.5-100] |
≥12 y | 570 | 98.6 [97.6-99.5] | 203 | 99.6 [98.9-100] | 140 | 98.6 [96.7-100] | 31 | 100 [88.9-100.0]d | 142 | 97.9 [96.3-99.5] | 34 | 93.2 [86.2-100] |
Region
| ||||||||||||
West Africa | 2,167 | 98.1 [97.6-98.7] | 959 | 97.8 [96.9-98.7] | 337 | 94.9 [92.6-97.2] | - | - | 257 | 95.3 [93.3-97.3] | - | - |
East Africa | 299 | 98.9 [97.8-100] | 24 | 100 [100-100] | 921 | 92.8 [91.2-94.4] | 869 | 93.4 [91.9-94.9] | 81 | 98.9 [97.8-100] | 127 | 89.5 [86.3-92.7] |
Rest of Africa | 615 | 98.6 [97.8-99.5] | - | - | 664 | 98.3 [97.3-99.2] | - | - | 124 | 97.1 [94.8-99.4] | - | - |
Asia | 305 | 95.5 [93.2-97.7] | - | - | 69 | 93.2 [87.5-99] | - | - | 112 | 93.8 [90.7-97] | 53 | 90.2 [83.3-97.1] |
S America | - | - | - | - | 30 | 100 [88.7-100]
d
| - | - | - | - | - | - |
Overall
|
3,386
|
98.1 [97.6-98.5]
|
983
|
97.9 [97-98.8]
|
2,021
|
95 [94.1-95.9]
|
869
|
93.4 [91.9-94.9]
|
574
|
96.1 [95-97.3]
|
180
|
92.1 [89.8-94.4]
|
Risk factors for recrudescence
Univariable analysis
|
Multivariable analysis
b
|
Population attributable risk
c
| |||||
---|---|---|---|---|---|---|---|
(N = 9,058)
| |||||||
Variable
|
Total
n
[
n
]
a
|
Crude HR [95% CI]
| p
-Value
|
Adjusted HR [95% CI]
| P
-Value
|
Freq.
|
PAR
|
Age (y)
| 9,095 (265) | 0.92 [0.89-0.96] | <0.001 | - | - | - | - |
Amodiaquine dose (5 mg/kg)
| 9,095 (265) | 0.94 [0.84-1.04] | 0.220 | 0.94 [0.84-1.05] | 0.280 | - | - |
Enrolment clinical variables
| |||||||
Parasitemia (per 10-fold) | 9,095 (265) | 1.46 [1.16-1.84] | 0.001 | 1.39 [1.1-1.74] | 0.005 | 10.4% | 3.7% |
Parasitemia >100,000 parasites/μl | 9,095 (265) | 1.41 [0.98-2.05] | 0.066 | - | - | - | - |
Fever (temp > 37.5°C) | 8,755 (252) | 1.05 [0.78-1.41] | 0.760 | - | - | - | - |
Hemoglobin (g/dl) | 6,895 (237) | 0.93 [0.87-1.00] | 0.055 | - | - | - | - |
Anemia (Hb < 10 g/dl) | 6,895 (237) | 1.37 [1.04-1.81] | 0.028 | - | - | - | - |
Gametocytes presence | 4,790 (99) | 1.04 [0.54-1.98] | 0.910 | - | - | - | - |
Underweight (WAZ < −2)d | 6,260 (616) | 0.87 [0.61-1.26] | 0.470 | - | - | - | - |
Gender
| |||||||
Female (reference) | 4,231 (126) | 1 | - | - | - | - | - |
Male | 4,702 (124) | 0.91 [0.71-1.16] | 0.450 | - | - | - | - |
Age category
| |||||||
≥12 y (reference) | 1,135 (12) | 1 | - | - | - | - | - |
<1 y | 782 (31) | 3.15 [1.46-6.78] | 0.004 | 3.93 [1.76-8.79] | 0.001 | 8.6% | 20.9% |
1 to <5 y | 5,645 (199) | 3.62 [1.83-7.18] | <0.001 | 4.47 [2.18-9.19] | <0.001 | 62.3% | 69.2% |
5 to <12 y | 1,533 (23) | 1.90 [0.91-3.98] | 0.088 | 2.03 [0.96-4.28] | 0.064 | 16.9% | 15.1% |
Drug formulation
| |||||||
FDC (reference) | 4,135 (70) | 1 | - | - | - | - | - |
Co-blistered NFDC | 1,256 (21) | 1.02 [0.52-2.00] | 0.950 | 1.38 [0.75-2.57] | 0.300 | 13.9% | 5.1% |
Loose NFDC-25 | 1,291(70) | 3.62 [1.79-7.30] | <0.001 | 3.51 [2.02-6.12] | <0.001 | 14.3% | 25.8% |
Loose NFDC-30e | |||||||
In Rukara/Kailahun/Kisumuf | 461 (59) | 8.41 [3.24-21.84] | <0.001 | 7.75 [4.07-14.76] | <0.001 | 5.1% | 26.3% |
Rest of the sites | 1,952 (45) | 1.34 [0.77-2.34] | 0.300 | 1.47 [0.91-2.38] | 0.110 | 21.1% | 8.3% |
Treatment supervision
| |||||||
Fully supervised (reference) | 8,530 (245) | 1 | - | - | - | - | - |
Partially supervised | 565 (20) | 1.37 [0.45-4.17] | 0.580 | - | - | - | - |
Parasite clearance
| |||||||
Day3 Parasitemia | 8,788 (252) | 2.17 [0.88-5.35] | 0.092 | - | - | - | - |
Region
| |||||||
Africa (reference)g | 8,624 (245) | 1 | - | - | - | - | - |
Asia | 434 (20) | 1.27 [1.83-3.55] | 0.700 | 7.39 [3.45-15.86] | <0.001 | 4.8% | 21.6% |
S. Americah | 37 (0) | - | - | - | - |
Safety parameters
Neutropenia
a, b
between day 1 and day 28
|
Anemia
a, b
between day 1 and day 28
|
Diarrhea between day 1 and day 7
|
Vomiting
c
between day 1 and day 7
|
Acute drug vomiting
| |
---|---|---|---|---|---|
AQ dose category (mg/kg)
d
| |||||
<25 | 7.0% (5/71) | 19.3% (79/410) | 4.7% (11/232) | 9.3% (24/258) | 4.7% (10/214) |
25 to <30 | 20.4% (33/162) | 24.1% (190/787) | 6.5% (56/857) | 9.7% (81/838) | 12.9% (80/622) |
30 to <35 | 17.9% (21/117) | 21.3% (132/621) | 5.8% (55/955) | 9.9% (92/933) | 11.3% (55/486) |
35 to <40 | 35.3% (30/85) | 24.8% (96/387) | 7.1% (49/693) | 11.3% (74/656) | 12.5% (54/433) |
40 to <45 | 30.8% (8/26) | 26.9% (58/216) | 7.4% (43/580) | 13.9% (76/546) | 14.7% (62/423) |
≥45 | 21.4% (6/28) | 25.7% (35/136) | 15.1% (76/504) | 12.9% (63/490) | 19.1% (33/173) |
Age category
| |||||
<1 y | 30.0% (15/50) | 49.6% (64/129) | 18.4% (52/282) | 6.6% (19/287) | 21.4% (27/126) |
1 to <5 y | 17.3% (44/255) | 28.0% (437/1,558) | 7.4% (189/2,565) | 8.7% (228/2,611) | 13.9% (230/1,655) |
5 to <12 y | 13.3% (14/105) | 12.4% (50/402) | 3.2% (16/505) | 15.8% (69/436) | 8.9% (26/292) |
≥12 y | 38.0% (30/79) | 8.3% (39/468) | 7.0% (33/469) | 24.3% (94/387) | 4.0% (11/278) |
Overall
| 21.1% (103/489) | 23.1% (590/2,557) | 7.6% (290/3,821) | 11.0% (410/3,721) | 12.5% (294/2,351) |