Abstract:
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BACKGROUND: Gametocytes are responsible for transmission of
malaria from human to mosquito. Artemisinin combination therapy
(ACT) reduces post-treatment gametocyte carriage, dependent upon
host, parasite and pharmacodynamic factors. The gametocytocidal
properties of antimalarial drugs are important for malaria
elimination efforts. An individual patient clinical data
meta-analysis was undertaken to identify the determinants of
gametocyte carriage and the comparative effects of four ACTs:
artemether-lumefantrine (AL), artesunate/amodiaquine (AS-AQ),
artesunate/mefloquine (AS-MQ), and
dihydroartemisinin-piperaquine (DP). METHODS: Factors associated
with gametocytaemia prior to, and following, ACT treatment were
identified in multivariable logistic or Cox regression analysis
with random effects. All relevant studies were identified
through a systematic review of PubMed. Risk of bias was
evaluated based on study design, methodology, and missing data.
RESULTS: The systematic review identified 169 published and 9
unpublished studies, 126 of which were shared with the WorldWide
Antimalarial Resistance Network (WWARN) and 121 trials including
48,840 patients were included in the analysis. Prevalence of
gametocytaemia by microscopy at enrolment was 12.1 %
(5887/48,589), and increased with decreasing age, decreasing
asexual parasite density and decreasing haemoglobin
concentration, and was higher in patients without fever at
presentation. After ACT treatment, gametocytaemia appeared in
1.9 % (95 % CI, 1.7-2.1) of patients. The appearance of
gametocytaemia was lowest after AS-MQ and AL and significantly
higher after DP (adjusted hazard ratio (AHR), 2.03; 95 % CI,
1.24-3.12; P = 0.005 compared to AL) and AS-AQ fixed dose
combination (FDC) (AHR, 4.01; 95 % CI, 2.40-6.72; P < 0.001
compared to AL). Among individuals who had gametocytaemia before
treatment, gametocytaemia clearance was significantly faster
with AS-MQ (AHR, 1.26; 95 % CI, 1.00-1.60; P = 0.054) and slower
with DP (AHR, 0.74; 95 % CI, 0.63-0.88; P = 0.001) compared to
AL. Both recrudescent (adjusted odds ratio (AOR), 9.05; 95 % CI,
3.74-21.90; P < 0.001) and new (AOR, 3.03; 95 % CI,
1.66-5.54; P < 0.001) infections with asexual-stage parasites
were strongly associated with development of gametocytaemia
after day 7. CONCLUSIONS: AS-MQ and AL are more effective than
DP and AS-AQ FDC in preventing gametocytaemia shortly after
treatment, suggesting that the non-artemisinin partner drug or
the timing of artemisinin dosing are important determinants of
post-treatment gametocyte dynamics. |