Early parasite clearance following artemisinin-based combination therapy among Ugandan children with uncomplicated Plasmodium falciparum malaria.
BACKGROUND
Artemisinin-based combination therapy (ACT) is widely recommended as first-line therapy for uncomplicated Plasmodium falciparum malaria worldwide. Artemisinin resistance has now been reported in Southeast Asia with a clinical phenotype manifested by slow parasite clearance. Although there are no reliable reports of artemisinin resistance in Africa, there is a need to better understand the dynamics of parasite clearance in African children treated with ACT in order to better detect the emergence of artemisinin resistance.


METHODS
Data from a cohort of Ugandan children four to five years old, enrolled in a longitudinal, randomized, clinical trial comparing two leading ACT, artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP), were analysed. For all episodes of uncomplicated P. falciparum malaria over a 14-month period, daily blood smears were performed for three days following the initiation of therapy. Associations between pre-treatment variables of interest and persistent parasitaemia were estimated using multivariate, generalized, estimating equations with adjustment for repeated measures in the same patient.


RESULTS
A total of 202 children were included, resulting in 416 episodes of malaria treated with AL and 354 episodes treated with DP. The prevalence of parasitaemia on days 1, 2, and 3 following initiation of therapy was 67.6, 5.6 and 0% in those treated with AL, and 52.2, 5.7 and 0.3% in those treated with DP. Independent risk factors for persistent parasitaemia on day 1 included treatment with AL vs DP (RR = 1.34, 95% CI 1.20-1.50, p < 0.001), having a temperature ≥38.0°C vs < 37.0°C (RR = 1.19, 95% CI 1.05-1.35, p = 0.007) and having a parasite density >20,000/μL vs <4,000/μL (RR = 3.37, 95% CI 2.44-4.49, p < 0.001). Independent risk factors for having persistent parasitaemia on day 2 included elevated temperature, higher parasite density, and being HIV infected.


CONCLUSIONS
Among Ugandan children, parasite clearance following treatment with AL or DP was excellent with only one of 752 patients tested having a positive blood slide three days after initiation of therapy. The type of ACT given, pre-treatment temperature, pre-treatment parasite density and HIV status were associated with differences in persistent parasitaemia, one or two days following therapy.


BACKGROUND
Current Controlled Trials Identifier NCT00527800.
Infectious Diseases Research Collaboration, Mulago Hospital Campus, PO Box 7475, Kampala, Uganda. marymkakuru@gmail.com.
Mary K
MK
Muhindo
Abel
A
Kakuru
Prasanna
P
Jagannathan
Ambrose
A
Talisuna
Emmanuel
E
Osilo
Francis
F
Orukan
Emmanuel
E
Arinaitwe
Jordan W
JW
Tappero
Frank
F
Kaharuza
Moses R
MR
Kamya
Grant
G
Dorsey
D000962:Antimalarials / Q000008:administration & dosage / Q000494:pharmacology*; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins / Q000008:administration & dosage / Q000494:pharmacology*; D002675:Child, Preschool; D004338:Drug Combinations; D004351:Drug Resistance; D004983:Ethanolamines / Q000008:administration & dosage / Q000494:pharmacology*; D005449:Fluorenes / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008137:Longitudinal Studies; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D018512:Parasitemia / Q000188:drug therapy* / Q000469:parasitology; D010963:Plasmodium falciparum / Q000187:drug effects*; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology*; D012307:Risk Factors; D014454:Uganda; D010879:Piperazines
D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; D011804:Quinolines; C039060:artenimol; C034759:piperaquine; D010879:Piperazines