Delayed anemia assessment in patients treated with oral artemisinin derivatives for uncomplicated malaria: a pooled analysis of clinical trials data from Mali

Abstract

Background: In sub-Saharan Africa, artemisinin-based combination therapy (ACT) and injectable artesunate are the first-line treatments for uncomplicated and severe Plasmodium falciparum malaria, respectively. However, recent studies suggest that delayed anaemia is associated with these treatments in non-immune travellers. This paper aimed to assess the risk factors associated with delayed anaemia after falciparum malaria treatment with artemisinin-containing drugs in malaria-endemic populations.

Methods: Pooled, individual malaria patient data were extracted from 13 clinical trials performed from 2002 to 2011 in various settings of Mali. Treatment regimens were artemether-lumefantrine, artesunate plus amodiaquine, artesunate plus sulphadoxine-pyrimethamine, artesunate plus sulphamethoxypyrazine-pyrimethamine, artesunate plus mefloquine, artesunate-pyronaridine, artesunate monotherapy, chloroquine, sulphadoxine-pyrimethamine, amodiaquine and sulphadoxine-pyrimethamine plus amodiaquine. Univariate and multivariate analyses were performed using the generalized linear and latent mixed model procedures to assess risk factors associated with haemoglobin concentration evolution and anaemia during the treatment follow-up.

Results: A total of 5,990 participants were recruited and followed from day 0 to day 28. The participants' median age was five years, ranging from three months to 70 years. There was a decrease in haemoglobin level on day 7 in all treatment arms, but the magnitude varied across treatments. There was a significant risk of haemoglobin level decrease on day 7 in the artemisinin-based therapy compared to the non-artemisinin treatments. The risk of haemoglobin concentration drop was associated with age group < five years old (0.61 g/dL 95% CI (0.71 to 0.51), p < 0.001), baseline high parasite density (0.43 g/dL 95% CI (0.51 to 0.35), p < 0.001) and treatment failure (0.40 g/dL 95% CI (0.59 to 0.20), p = 0.018), while high haemoglobin level at baseline was a protective factor (0.53 to 0.59) p < 0.001). No association was found between artemisinin-based therapy and severe delayed anaemia.

Conclusions: Oral artemisinin derivative treatments for uncomplicated P. falciparum malaria are associated with a transient and clinically moderate haemoglobin decrease by day 7 but not associated with a delayed severe anaemia.

Figure 1

Study sites. Study sites are indicated by red dots.

Figure 2

Multivariate analysis estimating late severe anaemia occurrence risk among patients who participated to all haemoglobin evaluation from day 0, 7, 14, and 28. n = 1,053, 956 and 941, respectively, for patients who participated to severe anaemia evaluation from day 7 to day 28, day 14 to day 28, and day 28. AL, artemether-lumefantrine; AS-AQ/AS-SP, artesunate plus amodiaquine/artesunate plus sulphadoxine-pyrimethamine; AS, artesunate; <5 years, <5 years old; PfDay0, Log Plasmodium falciparum density on day 0; TreatFail, Treatment failure outcome. Odds ratio were obtained from generalized linear and latent mixed model with binomial family using site as random effect; Covariates references were: CQ, AQ and SP for treatment, the age ≥5 years old for the age group, the 28-day cured parasite outcome after treatment for the treatment failure outcome, the baseline parasite density was log transformed and treated as continuous variable.