Malaria situation in the DRCandand

Management of Severe Malaria:The AQUAMAT Contribution of IV Artesunate in Reducing Mortalityg y

Dr Antoinette K. Tshefu. MD, MPH, PhDMMV’S Stakeholders’ MeetingDar es Salaam, 2nd June 2011

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DRC MAP

Malaria burden in the DRC

• ~ 70 million inhabitants (2009) for 2 345 000 km²• Endemic country for malaria• Intense and perennial malaria transmission• 100% population at risk of malaria with :- 97% living in stable transmission areasg- 3% living in unstable transmission areas (East)• Three species of Plasmodium : falciparum (more prevalent),

malariae and ovalemalariae and ovale• EIR (Entomological Inoculation Rate) : 2.8 to 620.5

bites/person/year.

AQUAMAT; An open randomised comparison of artesunate versus quinine in the treatment of severe falciparum malaria in African children

Sponsored by Oxford University DRC Site with Kinshasa

Funded by The Wellcome Trust

School of Public Health

Registration # ISRCTN50258054

Quality assurance & GCP

Original reports of: Quinine and Artesunate

Quinine- a cause for concern?

• Time-honored treatment of severe malaria• South East-Asia use of quinine problematic:q p

Quinine results in hypoglycaemia Significant issue of drug resistance

• Need to identify new agents• Need to identify new agents• In Africa- most quinine used in children

Quinine NOT associated with hypoglycaemia Q yp g yNo reports of drug resistance

OIL-based formulations: INTRAMUSCULAR ARTEMETHERStudies in Children with SEVERE MALARIA

Artemether (nmol/L)2000Poor uptake from IM injection- leads to

1200

1600 injection- leads to poor treatment effect!!!

800

1200

400

0

Time (h)0 4 8 12 16 20 24

Water based INTRAMUSCULAR ARTESUNATEIN severe malaria

4000Concentration (nmol/L)

3000

4000

2000

1000 DIHYDROARTEMISININ

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.50

ARTESUNATE

Time (h)

SEAQUAMAT

• 1,461 Asian adults and children (202)

• Quinine mortality: 164/731 (22.4%)

• Artesunate mortality: 107/730 (14.7%)

• 34.7% relative reduction in mortality

• Odd ti 0 6 (0 45 t 0 79) 0 0002• Odds ratio 0.6 (0.45 to 0.79) p=0.0002

Why might artesunate NOT work in Africa

• Disease ‘quicker’ in children-mortality difference occur after 2Disease quicker in children-mortality difference occur after 2 days

• possible patho physiological differences between Asian adults and African childhood severe malariaand African childhood severe malaria

• No quinine resistance in Africa• Many cases of ‘severe malaria’ are in fact bacterial sepsis

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The next question...

Compared to quinine, would artesunate reduce mortality Compared to quinine, would artesunate reduce mortality from severe malaria in afrom severe malaria in aAfrican children?African children?African children?African children?

AQUAMAT

• Large real-life study

• Mortality study

• Compared to quinine, does artesunate reduce mortality

from severe malaria in African children?

• Powered to detect a 25% fall in mortality from 8%

to 6% at 5% significance with 80% power

• Target recruitment 5,306 children

• Multi-centre, multi-country

Aquamat study sites

Study sites

•Mozambique: Beira •Kenya: Kilifi•The Gambia: Banjul •Ghana: Kumasi•Tanzania: KorogweMuheza •Uganda: Mbarare•Nigeria: Ilorin•Rwanda: Rwamagana

Nyanza•DRC: Kinshasa

Recruitment

• Total 5,425 children enrolled

11148 assessed5723 excluded

Trial profile

223 insufficient severity criteria4910 negative/invalid Optimal180 adequate antimalarial R/316 refused consent23 died before enrollment

5425 enrolled(Beira 663, Kilifi 442, Kumasi 436,

Muheza 921, Korogwe 540, Banjul 502, Ilorin 450, Ruanda 386, Mbarare 663,

23 died before enrollment25 below age or weight criteria46 other reasons

Kinshasa 422)

2712 artesunate 2713 quinine25 blood smear negative99 missing slide161149

17 blood smear negative112 missing slide

22 died before receiving drug4 missed early dose(s)8 unknown # doses of treatment3 didn’t fulfill entry criteria

161 excluded

149 excluded

g6 died before receiving drug7 missed early dose(s)7 unknown # doses of treatment2 withdrawn consent

2563 artesunate“per protocol”

2552 artesunate“per protocol”

Table 1 (part 1)Baseline characteristics according to treatment group

VariableQuinine

(N=2713)Artesunate(N=2712)

Gender; female (n %) 1295 (48%) 1315 (48%)Gender; female (n, %) 1295 (48%) 1315 (48%)

Age (y) 3.3 (2.3) 3.2. (2.2)

Fever before enrollment (days) 3.3 (2.0) 3.3 (2.2)

Coma before enrollment (h, median, range) 5 (0 to 72) 5 (0 to 96)

Pre-treatment with antimalarials (n, %)

None 1270 (47%) 1281 (47%)

Ineffective 268 (10%) 290 (11%)

Moderately 103 (4%) 97 (4%)

Effective 959 (35%) 938 (35%)

P. falciparum slide positive (n, %) 2550 (99%) 2552 (99%)

Severe Malaria* (n, %) 2338 (92%) 2280 (92%)

* severe malaria as defined in table 1

Table 1 (part 2)Baseline characteristics according to treatment group

Complications on admissionQuinine

(N=2713)Artesunate(N=2712)( ) ( )

Coma 997 (37%) 943 (35%)

Convulsions 879 (32%) 811 (30%)

Jaundice 59 (2%) 55 (2%)

Severe anaemia (<5g/dL) 693 (29%) 738 (30%)

Compensated shock 251 (9%) 233 (9%)

Decompensated shock 88 (3%) 90 (3%)

Severe acidosis (BE <-8 mmol/L) 975 (43%) 1009 (44%)

Hypoglycaemia (<3 mmol/L) 278 (10%) 277 (10%)

Respiratory distress** 428 (16%) 439 (16%)

Severe prostration*** 1668 (61%) 1683 (62%)

Blackwater fever 116 (4%) 121 (4%)

Hyperparasitaemia (>10%) 573 (24%) 584 (25%)yp p ( ) ( ) ( )

**respiratory distress defined as costal indrawing or respiratory insufficiency, ***severe prostration defined as inability to breastfeed under 6 months old or inability to sit in older children.

Table 1 (part 3)Baseline characteristics according to treatment group

Comorbidity (n, %)Quinine

(N=2713)Artesunate(N=2712)(N 2713) (N 2712)

Chronic disease 62 (2%) 49 (2%)

Immune compromised 49 (2%) 45 (2%)

Severe malnutrition 43 (2%) 54 (2%)Severe malnutrition 43 (2%) 54 (2%)

Suspected pneumonia 223 (8%) 224 (8%)

number confirmed by x-ray 29 (13%) 29 (13%)

Cllinical sepsis 355 (13%) 302 (11%)

number confirmed by culture 33 (9%) 32 (11%)

Suspected meningitis 166 (6%) 169 (6%)

Confirmed meningitis 3 (2%) 6 (4%)

Malnutrition 28 (1%) 34 (1%)

Other significant comorbidities 71 (3%) 80 (3%)Ot e s g ca t co o b d t es (3%) 80 (3%)

Table 1 (part 4)Baseline characteristics according to treatment group

Quinine ArtesunateBiochemistry results Quinine(N=2713)

Artesunate(N=2712)

Potassium (mmol/L) 4.1 (0.9) 4.1 (0.9)

Chloride (mmol/L) 105 (10) 105 (10)

Blood Urea Nitrogen (mmol/L) 6.1 (4.9) 6.1 (4.6)

Haemoglobin (g/dl) 7.0 (3.1) 6.8 (2.9)

pH 7 36 (0 14) 7 36 (0 14)pH 7.36 (0.14) 7.36 (0.14)

PaCO2 (mmHg) 28.2 (10.1) 27.9 (9.1)

HCO3 (mmol/L) 16.6 (5.7) 16.6 (5.6)

Base excess (mmol/L) -9 (7) -9 (7)

Anion gap (mmol/L) 17 (5) 17 (5)

ITT In-Hospital Mortality

• Quinine 297/2713 (11 0%)• Quinine -297/2713 (11.0%)

• Artesunate -230/2712 (8.5%) p=0.002

Relati e difference 22 5%22 5%Relative difference 22.5%22.5%(95%CI: 8.1% to 36.9%)

ITTIn-hospital Mortality

• Stratified Risk Ratio 0.78 (95%CI: 0.66 to 0.91; p=0.002)Test of homogeneity p=0 91Test of homogeneity p=0.91

• Stratified Odds Ratio 0.75(95%CI: 0.63 to 0.90; p=0.002)Test of homogeneity p=0.89

Kaplan‐Meier

Neurological sequelae

191 patients assessed

21 excluded4 unspecified behavioral problems

170 with neurological sequelae at discharge

p p9 no neurological problem confirmed4 pre-existing neurological problems4 mild motor impairment (children <18 m)

170 with neurological sequelae at discharge

41 lost to follow-up at day 2868 sequelae resolved by day 28

61 with neurological sequelae at day 28

10 Mild 8 Moderate 43 Severe (20 artesunate/ 23 quinine)10 Mild 8 Moderate 43 Severe (20 artesunate/ 23 quinine)30 Severe motor impairment14 Cortical blindness 9 Severe speech/ hearing impairment

Table 3Secondary  Outcomes

Quinine(n/total, %)

Artesunate(n/total, %)

OR(95% CI) p-value

Mortality, “per protocol” analysis

260/2552(10.2%)

208/2563(8.1%)

0.78(0.64 60 0.94) 0.009

Death or Sequelae at 28 297/2695 230/2689 0.78 0 006days (11.0%) (8.6%) (0.65 to 0.93) 0.006

Mortality ≤ 24 hours after admission

187/2708 (6.9%)

156/2707 (5.7%)

0.83(0.66 to 1.03) 0.087

Mortality > 24 hours after admission

105/2521 (4.2%)

69/2551 (2.7%)

0.64(0.47 to 0.87) 0.004

Malaria attributable mortality 288/2704 (10 7%)

223/2705 (8 2%)

0.75 (0 63 t 0 91) 0.002Malaria attributable mortality (10.7%) (8.2%) (0.63 to 0.91) 0.002

Case fatality in HIV positive children

19/61 (31%)

16/64 (25%)

0.74(0.33 to 1.62) 0.446

Table 4: Complications developing after start of treatment, according to treatment group

Variable Quinine(n/total, %)

Artesunate(n/total, %)

OR(95% CI) p-value

Development of coma after admission 92/1716 (5.4%)

65/1769 (3.7%)

0.68(0.49 to 0.94) 0.02

Deterioration of coma score 155/2713 (5 7%)

130/2712 (4 8%)

0.83(0 65 to 1 06) 0.13(5.7%) (4.8%) (0.65 to 1.06)

Convulsions developing or persisting > 6h after admission 273/2713 (10.1%) 224/2712

(8.3%)0.80

(0.66 to 0.97) 0.02

Hypoglycaemia after admission 75/2713 (2.8%)

48/2712 (1.8%)

0.63(0.43 to 0.91) 0.01

Severe anaemia (<5 g/dL) after admission 102/1631 (6 3%)

77/1581 (4 9%)

0.76(0 56 to 1 04) 0.08(6.3%) (4.9%) (0.56 to 1.04)

Black water fever after admission 18/2597 (0.7%)

30/2591 (1.2%)

1.69(0.94 to 3.05) 0.08

Development of coma, anaemia and black water fever was only assessed in patients with this condition not present on admission

Table 5: Additional treatments

Variable Quinine(n/total, %)

Artesunate(n/total, %)

OR(95% CI) p-value

0 98Blood transfusion 1495/2713 (55%) 1487/2712 (55%)

0.980.88 – 1.10

0.781

Fluid bolus 596/2713 (22%) 589/2712 (22%)0.98

0.85-1.130.983

≥2 anticonvulsants 196/2713 (7%)187/2712

(7%)0.95

0.77-1.170.952

Table 6: Time to events in surviving patients according to treatment group

Variable Quinine(median, IQR) N Artesunate

(median, IQR) N OR(95% CI) p-value

Time to discharge (days) 3.0 (2.0 to 5.0) 2412 3.0

(2.0 to 5.0) 2478 1.04(0.99 to 1.11) 0.136

Time to eat (hours)

12 (2 to 24) 2269 9

(0 to 24) 2358 0.99(0.93 to 1.06) 0.771

Time to sit unsupported (h )

22 (6 t 44) 2312 18

(6 t 42) 2373 1.02(0 95 t 1 08) 0.626(hours) (6 to 44) (6 to 42) (0.95 to 1.08)

Time to localize pain (hours) 12 (6 to 24) 726 12

(6 to 24) 698 0.87(0.78 to 0.98) 0.021

Time to speak (hours)

18 (11 to 36) 695 20 (

8 to 42) 664 0.88(0.79 to 0.99) 0.027

Time to localize pain and time to speak was assessed only for surviving patients with coma on admission (BCS<3 or GCS<11)

Conclusion

• Parenteral artesunate should replace quinine everywhere in the world as the first line treatment of severe falciparum malariatreatment of severe falciparum malaria

• There are approximately 8,000,000 severe malaria cases/ year (resulting in 800,000 deaths). If half of these patients received artesunate thenIf half of these patients received artesunate then 100,000 lives would be saved each year!

THANK YOU - AKSANTI

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