A randomized trial of artesunate-amodiaquine versus artemether-lumefantrine in Ghanaian paediatric sickle cell and non-sickle cell disease patients with acute uncomplicated malaria

Abstract

Background: Sickle cell disease (SCD) is a genetic disorder common in malaria endemic areas. In endemic areas, malaria is a major cause of morbidity and mortality among SCD patients. This suggests the need for prompt initiation of efficacious anti-malarial therapy in SCD patients with acute malaria. However, there is no information to date, on the efficacy or safety of artemisinin combination therapy when used for malaria treatment in SCD patients.

Methods: Children with SCD and acute uncomplicated malaria (n=60) were randomized to treatment with artesunate-amodiaquine (AA), or artemether-lumefantrine (AL). A comparison group of non-SCD children (HbAA genotype; n=59) with uncomplicated malaria were also randomized to treatment with AA or AL. Recruited children were followed up and selected investigations were done on days 1, 2, 3, 7, 14, 28, 35, and 42. Selected clinical and laboratory parameters of the SCD patients were also compared with a group of malaria-negative SCD children (n=82) in steady state.

Results: The parasite densities on admission were significantly lower in the SCD group, compared with the non-SCD group (p=0.0006). The parasite reduction ratio (PRR) was lower, clearance was slower (p<0.0001), and time for initial parasitaemia to decline by 50 and 90% were longer for the SCD group. Adequate clinical and parasitological response (ACPR) on day 28 was 98.3% (58/59) in the SCD group and 100% (57/57) in the non-SCD group. Corresponding ACPR rates on day 42 were 96.5% (55/57) in the SCD group and 96.4% (53/55) in the non-SCD group. The fractional changes in haemoglobin, platelets and white blood cell counts between baseline (day 0) and endpoint (day 42) were 16.9, 40.6 and 92.3%, respectively, for the SCD group, and, 12.3, 48.8 and 7.5%, respectively, for the non-SCD group. There were no differences in these indices between AA- and AL-treated subjects.

Conclusions: The parasite clearance of SCD children with uncomplicated malaria was slower compared with non-SCD children. AA and AL showed similar clinical and parasitological effects in the SCD and non-SCD groups. The alterations in WBC and platelet counts may have implications for SCD severity.

Trial registration: Current controlled trials ISRCTN96891086.

Figure 1

Trial profile. SCD = sickle cell disease; HbAA = non-SCD; AA = artesunate-amodiaquine; AL = artemether-lumefantrine.

Figure 2

Parasite clearance versus time (days) in the sickle cell disease (SCD) and non-SCD (HbAA) groups. SCD-mal + = sickle cell disease subjects with acute malaria group; Non-SCD (HbAA)-mal + = non-SCD subjects with acute malaria group.

Figure 3

Survival analysis showing parasite clearance per individual in the respective groups. SCD-AA = artesunate-amodiaquine-treated sickle cell disease subjects with acute malaria; SCD-AL = artemether-lumefantrine-treated sickle cell disease subjects with acute malaria; non-SCD = non sickle cell disease (haemoglobin genotype AA) subjects with acute malaria.

Figure 4

Haemoglobin levels on admission and follow up between the sickle cell disease and non-sickle cell disease subjects. Data are means and 95% confidence intervals (error bars). SCD = sickle cell disease subjects; HbAA = non-sickle cell disease subjects.

Figure 5

Haemoglobin levels on admission and follow-up between the artesunate-amodiaquine- and artemether-lumefantrine-treated sickle cell disease subjects. Data are means and 95% confidence intervals (error bars). SCD-AA = artesunate-amodiaquine-treated sickle cell disease subjects; SCD-AL = artemether-lumefantrine-treated sickle cell disease subjects.

Figure 6

Platelet counts on admission and follow-up between the sickle cell disease and non-sickle cell disease subjects. Data are means and 95% confidence intervals (error bars). SCD = sickle cell disease subjects; HbAA = non-sickle cell disease subjects.

Figure 7

Platelet counts on admission and follow-up between the artesunate-amodiaquine- and artemether-lumefantrine-treated sickle cell disease subjects. Data are means and 95% confidence intervals (error bars). SCD-AA = artesunate-amodiaquine-treated sickle cell disease subjects; SCD-AL = artemether-lumefantrine-treated sickle cell disease subjects.

Figure 8

Total white blood cell counts on admission and follow-up between the sickle cell disease and non-sickle cell disease subjects. Data are means and 95% confidence intervals (error bars). SCD = sickle cell disease subjects; HbAA = non-sickle cell disease subjects.

Figure 9

Total white blood cell counts on admission and follow-up between the artesunate-amodiaquine- and artemether-lumefantrine-treated sickle cell disease subjects. Data are means and 95% confidence intervals (error bars). SCD-AA = artesunate-amodiaquine-treated sickle cell disease subjects; SCD-AL = artemether-lumefantrine-treated sickle cell disease subjects.