Revisiting the circulation time of Plasmodium falciparum gametocytes: molecular detection methods to estimate the duration of gametocyte carriage and the effect of gametocytocidal drugs.
BACKGROUND
There is renewed acknowledgement that targeting gametocytes is essential for malaria control and elimination efforts. Simple mathematical models were fitted to data from clinical trials in order to determine the mean gametocyte circulation time and duration of gametocyte carriage in treated malaria patients.


METHODS
Data were used from clinical trials from East Africa. The first trial compared non-artemisinin combination therapy (non-ACT: sulphadoxine-pyrimethamine (SP) plus amodiaquine) and artemisinin-based combination therapy (ACT: SP plus artesunate (AS) or artemether-lumefantrine). The second trial compared ACT (SP+AS) with ACT in combination with a single dose of primaquine (ACT-PQ: SP+AS+PQ). Mature gametocytes were quantified in peripheral blood samples by nucleic acid sequence based amplification. A simple deterministic compartmental model was fitted to gametocyte densities to estimate the circulation time per gametocyte; a similar model was fitted to gametocyte prevalences to estimate the duration of gametocyte carriage after efficacious treatment.


RESULTS
The mean circulation time of gametocytes was 4.6-6.5 days. After non-ACT treatment, patients were estimated to carry gametocytes for an average of 55 days (95% CI 28.7 - 107.7). ACT reduced the duration of gametocyte carriage fourfold to 13.4 days (95% CI 10.2-17.5). Addition of PQ to ACT resulted in a further fourfold reduction of the duration of gametocyte carriage.


CONCLUSIONS
These findings confirm previous estimates of the circulation time of gametocytes, but indicate a much longer duration of (low density) gametocyte carriage after apparently successful clearance of asexual parasites. ACT shortened the period of gametocyte carriage considerably, and had the most pronounced effect on mature gametocytes when combined with PQ.
Bousema
Teun
T
Department of Infectious & Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK. teun.bousema@lshtm.ac.uk
Okell
Lucy
L
Shekalaghe
Seif
S
Griffin
Jamie T
JT
Omar
Sabah
S
Sawa
Patrick
P
Sutherland
Colin
C
Sauerwein
Robert
R
Ghani
Azra C
AC
Drakeley
Chris
C
D000293:Adolescent; D000655:Amodiaquine / Q000494:pharmacology / Q000627:therapeutic use; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins / Q000494:pharmacology / Q000627:therapeutic use; D000077332:Artesunate; D002353:Carrier State / Q000469:parasitology*; D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D004983:Ethanolamines / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005449:Fluorenes / Q000494:pharmacology / Q000627:therapeutic use; D005854:Germ Cells / Q000187:drug effects; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007630:Kenya / Q000453:epidemiology; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000453:epidemiology / Q000469:parasitology*; D008297:Male; D008954:Models, Biological; D018512:Parasitemia / Q000188:drug therapy / Q000453:epidemiology / Q000469:parasitology*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development* / Q000302:isolation & purification; D015995:Prevalence; D011319:Primaquine / Q000494:pharmacology / Q000627:therapeutic use; D011739:Pyrimethamine / Q000627:therapeutic use; D021161:Self-Sustained Sequence Replication / Q000379:methods*; D013413:Sulfadoxine / Q000627:therapeutic use; D013636:Tanzania / Q000453:epidemiology; D013997:Time Factors; D016896:Treatment Outcome
D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; D000655:Amodiaquine; C001205:fanasil, pyrimethamine drug combination; D000077332:Artesunate; D013413:Sulfadoxine; D011319:Primaquine; D011739:Pyrimethamine