Table 2 Published studies with the six-dose AL regimen in Africa

Bukirwa et al 2006 [16]

Uganda

Randomized, single-blind, single centre in children (1-10 years)

AL (n = 208)

ASAQ (n = 211)

Primary efficacy outcome was the 28-day risk of recurrent symptomatic malaria (AL = 27%;ASAQ = 42%) and recurrent parasitaemia (AL = 51%;ASAQ = 66%) both unadjusted for re-infection (both p = 0.001). When corrected for re-infection using PCR, the risks for both recurrent symptomatic malaria and parasitaemia were 0% for ASAQ and 1% for AL (equivalent to PCR-adjusted 28-day parasitological cure rates of 100% and 99%, respectively), illustrating the high rate of re-infection in the area studied.

Dorsey et al 2007 [17]

Uganda

Single-blind, randomized, single centre in children (1-10 years)

AL (n = 105)

AQSP (n = 111)

ASAQ (n = 113)

PCR-corrected 28-day cure rates of 99% with AL, 95.4% with ASAQ and 85.9% with AQSP. The differences between AL and AQSP, and between ASAQ and AQSP were statistically significant (p < 0.001 and p = 0.08, respectively).

Clearance of fever, sexual parasites and gametocytes were similar in the AL and ASAQ groups but slower in the AQSP group.

Gürkov et al 2008 [18]

Ethiopia

One centre, comparative in adults and children >5 years of age

AL (n = 30)

Quinine (n = 5)

Atovaquone/Proguanil (n = 32)

At 28-days, there were no treatment failures in the AL group, but the PCR-confirmed recrudescence rates in the quinine and atovaquone/proguanil groups were 9% and 6%, respectively.

Kabanywanyi et al 2007 [19]

Tanzania

Randomized, open-label, 2-centre in children (6-59 months)

AL (n = 99)

ASAQ (n = 76)

28-day PCR-corrected rates of adequate clinical and parasitological response were 100% for AL and 93.8% for ASAQ. Late parasitological failures, in all cases due to re-infection rather than recrudescence, occurred in 12% and 29% of each group, respectively.

Kamya et al 2007 [20]

Uganda

Single-blind, randomized, single centre in children (6 months to 10 years)

AL (n = 210)

DP (n = 211)

PCR-corrected risk of recurrent parasitaemia at Day 28 was significantly lower with DP than with AL (1.9% vs. 8.9%); this was also the case at Day 42 (6.9% vs. 16%). However, due to the complexity of infection in this area of very high transmission, leading to difficulty in distinguishing between new and recrudescent infections, the risks of recrudescence are probably overstated.

Times to clearance of fever and parasites were similar in the two treatment groups, although DP was associated with better control of gametocytes.

Mårtensson et al 2005 [21]

Zanzibar

Multicenter, randomized, open-label in children (6-59 months)

AL (n = 200)

ASAQ (n = 208)

PCR-corrected 28-day and 42-day parasitological cure rates of 97% and 92%, respectively, for AL and 91% and 88%, respectively, for ASAQ (p = 0.001 at 28 days and p = 0.045 at 42 days).

Parasite and fever clearance were rapid with both treatments, and gametocyte carriage was low in both groups.

Mårtensson et al 2007 [22]

Tanzania

Randomized, single centre, open-label study in children

AL (n = 50)

SP (n = 56)

PCR-corrected 42-day parasitological cure rates were 98% or 94% in the AL group (depending on whether standard or enhanced PCR was used); corresponding figures in the SP group were 70% and 66%, respectively.

Mohamed et al 2006 [23]

Sudan

2-centre, open-label, treatment assigned by centre, in children and adults

AL (n = 72)

ASSP (n = 71)

In this area of low malaria transmission both AL and ASSP were associated with adequate clinical and parasitological response rates of 100% at Day 28.

Mukhtar et al 2007 [24]

Sudan

Randomized, single centre, open-label study in children & adults

AL (n = 80)

ASSP (n = 77)

PCR-corrected rates of adequate clinical and parasitological response of 93.4% for ASSP and 91.3% for AL. The treatment regimen used was not clear.

Mutabingwa et al 2005 [25]

Tanzania

Randomized, single centre, open-label study in children

AL (n = 519)

ASAQ (n = 515)

AQSP (n = 507)

AQ (n = 270)

PCR-corrected 28-day parasitological cure rates were 51.6% for AQ, 65.5% for AQSP, 88.8% for ASAQ, and 97.2% for AL.

Recruitment to the AQ group was stopped early by the trial's data and safety monitoring board due to a high treatment failure rate.

Yeka et al 2008 [26]

Uganda

Randomized, one centre, single-blinded, in children aged 6 months to 10 years

AL (n = 227)

DP (n = 234)

At 42 days there was no statistically significant difference in the risk of recrudescence (5.8% for AL vs. 2.0% for DP; risk difference = 3.8%, 95% CI 0.2-7.8%), although recurrent parasitaemia (uncorrected for re-infection) was more frequent with AL (33.2% vs. 12.2% for DP).

Mulenga et al 2006 [27]

Zambia

Randomized, open-label, multicentre, in adults

AL (n = 485)

SP (n = 486)

AL was associated with significantly faster clearance of fever, parasitaemia and gametocytes than SP, and a higher Day 45 PCR-corrected cure rate (94.6% vs. 80.7%, p < 0.001).

Toovey 2008 [28]

Mozambique

Non-comparative, open-label, single centre in adults

AL (n = 54)

28-day parasitological cure rate of 100%.

Adjei et al 2008 [29]

Ghana

Randomized, open label

AL (n = 111)

AS+AQ (n = 116)

For the AL group, adequate clinical and parasitological response was reported in 97.1% patients at Day 14 and 94.2% at Day 28; corresponding figures for ASAQ were 98.2% and 95.3%.

Falade et al 2008 [30]

Nigeria

Randomized, open label, single centre in children (6 months to 10 years)

AL (n = 66)

ASAQ (n = 66)

PCR-corrected 28-day parasitological cure rates of 100% for AL and 98.4% for ASAQ.

Faye et al 2007 [31]

Senegal

Randomized, open-label, multicentre in children and adults

ASAQ (n = 360)

AQSP (n = 161)

MAS (n = 145)

AL (6 dose) (n = 149)

AL (four-dose) (n = 140)

PCR-corrected 28-day parasitological cure rates were 100% for all treatments other than AL four-dose (96.4%). Parasite clearance was observed to be more rapid with all ACTs than with AQSP.

Initial reduction of gametocyte carriage also appeared to be more rapid with the ACTs than with AQSP, although all patients were free of gametocytes by day 21.

Koram et al 2005 [32]

Ghana

Multicentre, randomized, open-label in children (6-59 months)

AL (n = 51)

CQ (n = 36)

SP (n = 27)

ASAQ (n = 54)

PCR-corrected 28-day cure rates of 25% for chloroquine, 60% for SP, 100% for ASAQ, and 97.5% for AL.

Meremikwu et al 2006 [33]

Nigeria

Randomized, open-label, single centre, in children (6-59 months)

AL (n = 60)

ASAQ (n = 59)

Both treatments highly effective with similar rates of adequate clinical and parasitological response, early treatment failure, late clinical failure and late parasitological failure at 14 days.

Owusi-Agyei et al 2008 [34]

Ghana

Randomized, open label in children aged 6 months to 10 years

AL (n = 223)

ASAQ (n = 220)

ASCD (n = 178)

Per-protocol analysis showed a lower PCR-corrected parasitological and clinical failure rate at day 28 in the ASAQ group (6.6%) compared with the AL group (13.8%) or ASCD group (13.8%).

Sagara et al 2006 [35]

Mali

Randomized, single centre, open-label study in children (≥ 6 months) and adults

AL (n = 303)

AS plus sulphamethoxypyrazine plus pyrimethamine (n = 303)

28-day PCR-corrected parasitological cure rates were 100% for AS plus sulphamethoxypyrazine plus pyrimethamine, and 99% for AL.

Gametocyte clearance was similar in the two treatment groups.

Sowunmi et al 2007 [36]

Nigeria

Randomized, open-label, single centre, in children (≤ 10 years)

AL (n = 90)

AQ plus sulphalene plus pyrimethamine (n = 91)

PCR-corrected parasitological cure rates at 42 days were 93.3% for AL and 98.9% for AQ plus sulphalene plus pyrimethamine.

Sutherland et al 2005 [37]

Gambia

Randomized, single centre, single-blind, in children (1-10 years)

AL (n = 406)

CQSP (n = 91)

PCR-corrected 28-day cure rates were 96.1% for AL and 91.1% for CQSP.

AL-treated patients were statistically significantly less likely to carry gametocytes at Day 28 than those who received CQSP (8% vs. 49%, p < 0.0001), and carriers in the AL group harboured gametocytes at lower densities, for shorter periods (0.3 d vs. 4.2 d, p < 0.0001) and were less infectious to mosquitoes at day 7 (p < 0.001) than carriers in the CQSP group.

Zongo et al 2007 [38]

Burkina Faso

Multicentre, randomized, open-label in children (6 months to 10 years)

AL (n = 261)

AQSP (n = 260)

The crude (uncorrected for re-infection) risk of recurrent malaria at 28 days was significantly higher with AL than AQSP (10.2% vs. 1.7%, p < 0.0001); PCR correction gave risks of recurrent malaria of 1.2% and 0.4%, with the between-group difference not statistically significant.

Zongo et al 2007 [39]

Burkina Faso

Multicentre, randomized, open-label in children (≥ 6 months)

AL (n = 188)

AQSP (n = 184)

DP (n = 187)

PCR-corrected risks of re-infection at Day 28 were AL, 3.4%; DP, 2.2% and AQSP, 3.9%.

Fanello et al 2007 [40]

Rwanda

Randomized, open-label, 2-centre in children (12-59 months)

AL (n = 251)

AQSP (n = 249)

AL was associated with a statistically significantly higher rate of PCR-adjusted adequate clinical and parasitological response at Day 28 than AQSP (96.8% vs. 79.4%, p < 0.0001).

Gametocyte carriage was significantly lower in the AL group at all post-baseline time points.

Guthman et al 2006 [41]

Angola

Randomized, open-label, single centre in children (6-59 months)

AL (n = 61)

ASAQ (n = 64)

PCR-corrected 28-day parasitological cure rates were 100% for both AL and ASAQ.

Ndayiragije et al 2004 [42]

Burundi

Multicentre, randomized, open-label in children (<5 years)

AL (n = 142)

ASAQ (n = 153)

14-day rates of adequate clinical and parasitological response were similar between treatment groups:AL = 99.3%;ASAQ = 95.3%.

Effects on gametocyte carriage were also similar between treatments.

van den Broek et al 2006 [43]

Republic of Congo

Randomized, single centre, open-label study in children (6-59 months)

AL (n = 106)

ASAQ (n = 101)

ASSP (n = 91)

PCR-corrected 28-day parasitological cure rates were 100% for AL, 98.5% for ASAQ and 90.1% for ASSP. The differences in cure rates between AL and ASSP, and between ASAQ and ASSP, were statistically significant.

Clearance of asexual parasites, gametocytes and fever were rapid in all three treatment groups.