Effects of liver-stage clearance by Primaquine on gametocyte carriage of Plasmodium vivax and P. falciparum

Abstract

BackgroundPrimaquine (PQ) is the only currently licensed antimalarial that prevents Plasmodium vivax (Pv) relapses. It also clears mature P. falciparum (Pf) gametocytes, thereby reducing post-treatment transmission. Randomized PQ treatment in a treatment-to-reinfection cohort in Papua New Guinean children permitted the study of Pv and Pf gametocyte carriage after radical cure and to investigate the contribution of Pv relapses.MethodsChildren received radical cure with Chloroquine, Artemether-Lumefantrine plus either PQ or placebo. Blood samples were subsequently collected in 2-to 4-weekly intervals over 8 months. Gametocytes were detected by quantitative reverse transcription-PCR targeting pvs25 and pfs25.ResultsPQ treatment reduced the incidence of Pv gametocytes by 73%, which was comparable to the effect of PQ on incidence of blood-stage infections. 92% of Pv and 79% of Pf gametocyte-positive infections were asymptomatic. Pv and to a lesser extent Pf gametocyte positivity and density were associated with high blood-stage parasite densities. Multivariate analysis revealed that the odds of gametocytes were significantly reduced in mixed-species infections compared to single-species infections for both species (ORPv = 0.39 [95% CI 0.25–0.62], ORPf = 0.33 [95% CI 0.18–0.60], p<0.001). No difference between the PQ and placebo treatment arms was observed in density of Pv gametocytes or in the proportion of Pv infections that carried gametocytes. First infections after blood-stage and placebo treatment, likely caused by a relapsing hypnozoite, were equally likely to carry gametocytes than first infections after PQ treatment, likely caused by an infective mosquito bite.ConclusionPv relapses and new infections are associated with similar levels of gametocytaemia. Relapses thus contribute considerably to the Pv reservoir highlighting the importance of effective anti-hypnozoite treatment for efficient control of Pv.Trial registrationClinicalTrials.gov NCT02143934

Plasmodium vivax and Plasmodium falciparum infection dynamics: re-infections, recrudescences and relapses

“…Addressing the knowledge gap on the duration of blood-stage P. vivax infections could have substantial clinical and public health value. The effectiveness of drug treatment strategies for reducing malaria transmission will depend on the duration of blood-stage infection: if the duration of infection is unknown, then the number of transmission events of gametocytes from humans to mosquitoes prevented by treatment can’t be assessed [ 39 , 40 ]. If blood-stage P. vivax parasitaemia is sustained by multiple short infections, then clearing a single infection with a blood-stage drug such as artemisinin combination therapy (ACT) will cause very little reduction in transmission.…”

Plasmodium vivax molecular diagnostics in community surveys: pitfalls and solutions

“…Treatment of asymptomatic P. vivax infections has two aims: firstly, to target gametocytes to prevent onward transmission to mosquitoes and, secondly, to target dormant liver stages to prevent relapses. Blood-stage infections originating from relapses frequently carry gametocytes and, thus, likely also contribute to transmission [ 46 ].…”

Prevalence and Force of Plasmodium Vivax and Plasmodium Falciparum Blood Stage Infection and Associated Clinical Malaria Burden in the Brazilian Amazon

“…Individual databases were combined in Microsoft Access 2010. For incidence calculations (molFOB and clinical malaria incidence), subject data were censored on the last visit before two consecutively missed scheduled follow-up visits in order to reduce bias [28]. Differences in proportions were tested for statistical signi cance using the McNemar X2 test with continuity correction.…”

“…molFOB for P. vivax was determined for both genetic markers combined. Negative binomial regression models were used to assess the in uence of different risk-factors on the incidence of P. vivax and P. falciparum gametocyte positivity as previously described, using positivity counts and times-at-risk over the entire period of observation [28].…”