Background
Methods
Identification of studies for potential inclusion
Individual patient data
Definition of parameters assessed
Anaemia
Parasite positivity
Malaria transmission intensity
Ethical approval
Statistical analysis
Assessment of risk of potential bias
Results
Characteristics of eligible studies
Baseline characteristics
Baseline characteristics | AL (2002–2012) | AS-AQ (1999–2012) | DP (2003–2011) | Total (1999–2012) |
---|---|---|---|---|
Patients (N) | 13,664 (46.3 %) | 11,337 (38.4 %) | 4,492 (15.2 %) | 29,493 |
Female | 6,437 (47.1 %) | 5,322 (46.9 %) | 2,123 (47.3 %) | 13,882 (47.1 %) |
Age | ||||
Mean age ± SD (years) | 7.4 ± 9.22 | 6.6 ± 8.60 | 4.9 ± 7.51 | 6.7 ± 8.78 |
<1 year | 795 (5.8 %) | 842 (7.4 %) | 447 (10.0 %) | 2,084 (7.1 %) |
1 to <5 years | 7,183 (52.6 %) | 6,324 (55.8 %) | 3,185 (70.9 %) | 16,692 (56.6 %) |
5 to <12 years | 3,184 (23.3 %) | 2,357 (20.8 %) | 432 (9.6 %) | 5,973 (20.3 %) |
≥12 years | 2,478 (18.1 %) | 1,801 (15.9 %) | 427 (9.5 %) | 4,706 (16.0 %) |
Geographic region | ||||
East Africa | 6,040 (44.2 %) | 2,920 (25.8 %) | 2,229 (49.6 %) | 11,189 (37.9 %) |
West Africa | 6,481 (47.4 %) | 6,749 (59.5 %) | 1,302 (29.0 %) | 14,532 (49.3 %) |
Central Africa | 483 (3.5 %) | 758 (6.7 %) | 174 (3.9 %) | 1,415 (4.8 %) |
South Africa | 660 (4.8 %) | 910 (8.0 %) | 787 (17.5 %) | 2,357 (8.0 %) |
Transmission settings | ||||
High | 4,836 (35.4 %) | 4,062 (35.8 %) | 1,876 (41.8 %) | 10,774 (36.5 %) |
Low/moderate | 8,828 (64.6 %) | 7,275 (64.2 %) | 2,616 (58.2 %) | 18,719 (63.5 %) |
Enrolment clinical parameters | ||||
Mean body weight ± SD (kg) | 21.2 ± 16.23 | 19.5 ± 15.26 | 16.3 ± 13.72 | 19.8 ± 15.59 |
Median parasitaemia (IQR) | 19,260 (5,930–48,260) | 20,000 (6,080–52,480) | 25,540 (8,320–59,830) | 20,200 (6,320–51,520) |
Parasitaemia >100,000/μL | 8.4 % (1,152/13,664) | 10.7 % (1,209/11,337) | 11.7 % (527/4,492) | 9.8 % (2,888/29,493) |
Mean haemoglobin ± SD (g/dl) | 10.3 ± 2.17 | 9.7 ± 2.10 | 9.6 ± 1.86 | 9.9 ± 2.11 |
Gametocytes presence | 8.2 % (868/10,649) | 11.1 % (821/7,428) | 9.1 % (394/4,325) | 9.3 % (2,083/22,402) |
Elevated temperature (>37.5 °C) | 61.9 % (7,861/12,691) | 67.3 % (7,461/11,092) | 63.7 % (2,814/4,419) | 64.3 % (18,136/28,202) |
Anaemia | ||||
Moderate | 44 % (4,246/9,650) | 48.6 % (3,761/7,734) | 52.7 % (2,159/4,095) | 47.3 % (10,166/21,479) |
Severe | 6.9 % (666/9,650) | 10.1 % (780/7,734) | 7.5 % (306/4,095) | 8.2 % (1,752/21,479) |
Observed parasite positivity rates (PPRs) on days 1, 2 and 3
AL | AS-AQc | DP | Overall | |
---|---|---|---|---|
Day 1 | ||||
PPR (%)a | 59.3 % (4,721/7,966) (95 % CI: 52.2–66.3) | 60.3 % (3,463/5,746) (95 % CI: 54.7–65.8) | 59.8 % (1,915/3,204) (95 % CI: 50.3–69.2) | 59.7 % (10,099/16,916) (95 % CI: 54.5–64.9) |
Number of study sitesb | 81 | 52 | 25 | 158 |
Median PPR (IQR; range)b | 61.8 % (35.5–79.1; 0–97.6) | 58.8 % (47.1–77.0; 0.0–96.3) | 53.8 % (32.4–69.4; 18.3–93.0) | 57.9 % (36.1–77.0; 0.0–97.6) |
Day 2 | ||||
PPR (%)a | 5.9 % (729/12,255) | 7.2 % (784/10,821) | 7.7 % (340/4,420) | 6.7 % (1,853/27,496) |
Number of study sitesb | 100 | 79 | 36 | 215 |
Median PPR (IQR; range)b | 2.9 (1–8.3; 0.0–42.4) | 5.6 % (1.5–12.3; 0.0–88.1) | 3.9 % (0.4–6.7; 0.0–39.1) | 3.3 % (1.2–10.2; 0.0–88.1) |
Day 3 | ||||
PPR (%)a | 0.6 % (76/13,004) | 1.3 % (143/11,142) | 0.8 % (34/4,434) | 0.9 % (253/28,580) |
Number of study sitesb | 105 | 84 | 36 | 225 |
Median PPR (IQR; range)b | 0.0 % (0.0–0.9; 0.0–7.8) | 0.3 % (0.0–1.6; 0.0–30.7) | 0.0 % (0.0–0.5; 0.0–7.7) | 0.0 % (0.0–0.7;0.0–30.7) |
Study site (country) | Year | Treatment | Day 3 PPR (95 % CI)a |
---|---|---|---|
New Halfa (Sudan) | 2006 | AL | 3.0 % (1/33) (0.5–15.3) |
ELWA Hospital (Liberia) | 2007 | AL | 3.4 % (2/58) (0.9–11.7) |
JFK Hospital (Liberia) | 2007 | AL | 3.8 % (2/53) (1.0–12.8) |
Bagamoyo (Tanzania) | 2004 | AL | 4.0 % (2/50) (1.1–13.5) |
Afokang (Nigeria) | 2007–08 | AL | 5.9 % (10/170) (3.2–10.5) |
Ndumo (South Africa) | 2002 | AL | 6.0 % (6/100) (2.8–12.5) |
San Pedro (Côte d’Ivoire) | 2012 | AL | 6.5 % (2/31) (1.8–20.7) |
Gedaref (Sudan) | 2006 | AL | 7.8 % (4/51) (3.1–18.5) |
Andapa (Madagascar) | 2007 | AS-AQ (loose NFDC) | 3.3 % (1/30) (0.6–16.7) |
Gaya (Niger) | 2011 | AS-AQ (FDC) | 3.9 % (3/77) (1.3–10.8) |
Grand Gedeh County (Liberia) | 2010–11 | AS-AQ (FDC) | 3.9 % (4/102) (1.5–9.7) |
Dabola (Guinea) | 2004 | AS-AQ (loose NFDC) | 4.5 % (5/110) (1.9–10.2) |
Afokang (Nigeria) | 2007–08 | AS-AQ (FDC) | 5.2 % (9/173) (2.8–9.6) |
Malakal (Sudan) | 2003 | AS-AQ (loose NFDC) | 5.3 % (7/131) (2.6–10.6) |
Kuito (Angola) | 2003 | AS-AQ (loose NFDC) | 5.4 % (5/93) (2.3–11.9) |
Kailahun (Sierra Leone) | 2004 | AS-AQ (loose NFDC) | 5.6 % (7/125) (2.7–11.1) |
Mlomp (Senegal) | 1999 | AS-AQ (loose NFDC) | 5.8 % (9/154) (3.1–10.7) |
Richard Toll (Senegal) | 2003 | AS-AQ (loose NFDC) | 7.1 % (3/42) (2.5–19.0) |
Miandrivazo (Madagascar) | 2006 | AS-AQ (loose NFDC) | 10.3 % (7/68) (5.1–19.8)b |
Yaoundé (Cameroon) | 2005 | AS-AQ (coblistered NFDC) | 30.7 % (31/101) (22.5–40.3)b |
Manhiça (Mozambique) | 2005–06 | DP | 4.0 % (12/299) (2.3–6.9) |
Afokang (Nigeria) | 2007–08 | DP | 7.7 % (11/142) (4.4–13.3) |
Risk factors associated with the parasite positivity status
Univariable analysis | Multivariable analysisc | |||||
---|---|---|---|---|---|---|
Variable | N (n)a | Random effectsb | Crude OR (95 % CI) | P value | Adjusted OR (95 % CI) | P value |
Baseline parasitaemia (2-fold rise) | 27,496 (1,853) | 2.31 | 1.30 (1.26–1.34) | <0.001 | 1.27 (1.24–1.31) | <0.001 |
Baseline anaemia | ||||||
Non-anaemic (reference)d | 8,838 (544) | 2.14 | 1 | - | - | - |
Moderate | 9,652 (714) | 1.07 (0.94–1.22) | 0.274 | 1.07 (0.94–1.22) | 0.289 | |
Severe | 1,668 (124) | 1.24 (0.99–1.55) | 0.056 | 1.33 (1.06–1.67) | 0.014 | |
Unknown | 7,338 (471) | - | - | - | - | |
Gametocytes presence | ||||||
No (reference) | 18,672 (1,358) | 2.08 | 1 | - | - | - |
Yes | 1,979 (102) | 0.95 (0.74–1.2) | 0.650 | - | - | |
Febrile on presentation (temperature >37.5 °C) | ||||||
No (reference) | 9,355 (433) | 2.06 | 1 | - | - | - |
Yes | 17,217 (1,412) | 1.72 (1.52–1.95) | <0.001 | 1.46 (1.28–1.66) | <0.001 | |
Gendere | ||||||
Female (reference) | 12,873 (835) | 2.22 | 1 | - | - | - |
Male | 13,995 (982) | 1.11 (1.00–1.23) | 0.052 | - | - | |
Age category | ||||||
≥12 years (reference) | 4,245 (202) | 2.22 | 1 | - | - | - |
<1 year | 2,014 (139) | 1.89 (1.40–2.57) | <0.001 | 1.49 (1.09–2.05) | 0.013 | |
1 to <5 years | 15,677 (1,176) | 1.94 (1.52–2.46) | <0.001 | 1.54 (1.21–1.97) | 0.001 | |
5 to <12 years | 5,528 (334) | 1.49 (1.20–1.85) | <0.001 | 1.25 (1.00–1.56) | 0.048 | |
Transmission settings | ||||||
High (reference) | 10,368 (455) | 2.12 | 1 | - | - | - |
Low/moderate | 17,128 (1,398) | 1.50 (0.88–2.55) | 0.135 | 1.88 (1.09–3.24) | 0.024 | |
Treatmentf | ||||||
DP (reference) | 4,420 (340) | 2.12 | 1 | - | - | - |
AL | 12,255 (729) | 1.19 (1.00–1.42) | 0.050 | 1.21 (1.01–1.44) | 0.040 | |
ASAQ-FDC | 4,997 (246) | 0.94 (0.75–1.19) | 0.619 | 0.90 (0.71–1.14) | 0.388 | |
ASAQ-coblistered NFDC | 1,574 (167) | 1.80 (0.84–3.85) | 0.130 | 1.87 (0.86–4.04) | 0.113 | |
ASAQ-loose NFDC | 4,250 (371) | 1.62 (1.18–2.22) | 0.003 | 1.46 (1.05–2.01) | 0.022 |
Univariable analysis | Multivariable analysisc | |||||
---|---|---|---|---|---|---|
Variable | N (n)a | Random effectsb | Crude OR (95 % CI) | P value | Adjusted OR (95 % CI) | P value |
Baseline parasitaemia (2-fold rise) | 28,580 (253) | 2.57 | 1.18 (1.10–1.28) | <0.001 | 1.16 (1.08–1.25) | <0.001 |
Baseline anaemia | ||||||
Non-anaemic (reference)d | 9,368 (60) | 2.50 | 1 | - | - | - |
Moderate | 9,926 (86) | 1.14 (0.80–1.61) | 0.473 | 1.14 (0.80–1.61) | 0.476 | |
Severe | 1,697 (23) | 1.94 (1.15–3.25) | 0.012 | 2.04 (1.21–3.44) | 0.008 | |
Unknown | 7,589 (84) | 1.08 (0.55–2.13) | 0.827 | - | - | |
Gametocytes presence | ||||||
No (reference) | 19,561 (168) | 3.20 | 1 | - | - | - |
Yes | 2,038 (17) | 1.10 (0.63–1.91) | 0.747 | - | - | |
Febrile on presentation (temperature >37.5 °C) | ||||||
No (reference) | 9,874 (46) | 2.27 | 1 | - | - | - |
Yes | 17,678 (207) | 1.68 (1.19–2.38) | 0.003 | 1.50 (1.06–2.13) | 0.022 | |
Gender | ||||||
Female (reference) | 13,439 (106) | 2.56 | 1 | - | - | - |
Male | 14,511 (142) | 1.22 (0.94–1.58) | 0.134 | - | - | |
Age category | ||||||
≥12 years (reference) | 4,639 (36) | 2.55 | 1 | - | - | - |
<1 year | 2,027 (20) | 1.51 (0.75–3.03) | 0.247 | 1.25 (0.62–2.55) | 0.530 | |
1 to <5 years | 16,060 (130) | 1.23 (0.72–2.10) | 0.453 | 1.09 (0.64–1.87) | 0.753 | |
5 to <12 years | 5,818 (66) | 1.74 (1.09–2.76) | 0.019 | 1.56 (0.98–2.48) | 0.061 | |
Transmission settings | ||||||
High (reference) | 10,377 (66) | 2.38 | 1 | - | - | - |
Low/moderate | 18,203 (187) | 2.34 (1.14–4.80) | 0.021 | 2.71 (1.38–5.36) | 0.004 | |
Treatmente | ||||||
DP (reference) | 4,434 (34) | 2.01 | 1 | - | - | - |
AL | 13,004 (76) | 0.93 (0.57–1.51) | 0.765 | 0.93 (0.57–1.52) | 0.774 | |
ASAQ-FDC | 4,999 (27) | 0.70 (0.38–1.31) | 0.269 | 0.67 (0.36–1.25) | 0.206 | |
ASAQ-coblistered NFDC | 1,851 (44) | 2.23 (0.69–7.22) | 0.183 | 2.87 (0.89–9.27) | 0.078 | |
ASAQ-loose NFDC | 4,292 (72) | 2.27 (1.12–4.60) | 0.023 | 2.27 (1.14–4.51) | 0.020 |
Effect of weight adjusted (mg/kg) artemisinin components
Derivation of day 3 PPR threshold for suspected diminished artemisinin susceptibility
Variable | AL | ASAQ-FDC | DP | |||
---|---|---|---|---|---|---|
Day 3 PPR (95 % CI) | Maximum predicted riska | Day 3 PPR (95 % CI) | Maximum predicted riska | Day 3 PPR (95 % CI) | Maximum predicted riska | |
Age category | ||||||
<1 year | 0.79 (0.00–1.67) | 6.50 | 0.67 (0.00–2.00) | 7.69 | 0.68 (0.00–1.45) | 6.00 |
1 to <5 years | 0.54 (0.28–0.79) | 4.30 | 0.70 (0.19–1.21) | 6.00 | 0.83 (0.00–1.65) | 6.35 |
5 to <12 years | 0.69 (0.26–1.11) | 6.00 | 0.32 (0.00–0.76) | 4.11 | 0.70 (0.07–1.34) | 6.00 |
≥12 years | 0.49 (0.11–0.88) | 4.76 | 0.13 (0.00–0.40) | 4.00 | 0.48 (0.00–1.06) | 5.66 |
Transmission | ||||||
High | 0.20 (0.03–0.37) | 4.00 | 0.27 (0.06–0.48) | 4.00 | 0.05 (0.00–0.15) | 2.00 |
Low/moderate | 0.79 (0.43–1.15) | 6.00 | 0.65 (0.09–1.22) | 6.00 | 1.28 (0.27–2.29) | 8.00 |
Parasitaemia (x 1,000 parasites/μl) | ||||||
<10 | 0.39 (0.18–0.60) | 4.00 | 0.43 (0.00–0.91) | 4.92 | 0.87 (0.00–1.81) | 7.02 |
10 to <50 | 0.58 (0.30–0.86) | 4.62 | 0.35 (0.00–0.72) | 4.00 | 0.54 (0.01–1.08) | 5.77 |
50 to <100 | 0.81 (0.32–1.30) | 6.00 | 1.01 (0.20–1.83) | 7.02 | 0.86 (0.00–1.85) | 7.14 |
≥100 | 1.04 (0.35–1.74) | 6.67 | 1.12 (0.00–2.25) | 8.00 | 1.15 (0.13–2.17) | 8.00 |
Study sample size | ||||||
<50 | 1.02 (0.12–1.92) | 10.34 | 0.78 (0.00–2.00) | 10.71 | 0.00 (0.00–7.71) | 20.68 |
50 to <100 | 0.72 (0.30–1.13) | 6.00 | 0.55 (0.00–1.53) | 6.00 | 0.25 (0.00–0.50) | 4.00 |
100 to <200 | 0.90 (0.34–1.45) | 4.62 | 0.88 (0.08–1.68) | 5.00 | 1.43 (0.00–3.03) | 7.01 |
≥200 | 0.25 (0.05–0.45) | 1.75 | 0.18 (0.02–0.35) | 1.50 | 0.70 (0.00–1.73) | 4.00 |
Overall | 0.58 (0.34–0.82) | 4.41 | 0.54 (0.14–0.94) | 5.08 | 0.77 (0.11–1.42) | 6.00 |