Gametocyte Dynamics and the Role of Drugs in Reducing the Transmission Potential of Plasmodium vivax

Douglas, Nicholas M.; Simpson, Julie A; Phyo, Aung Pyae; Siswantoro, Hadjar; Hasugian, Armedy Ronny; Kenangalem, Enny; Poespoprodjo, Jeanne Rini; Singhasivanon, Pratap; Anstey, Nicholas M.; White, Nicholas J.; Tjitra, Emiliana; Nosten, François; Price, Ric N.

doi:10.1093/infdis/jit261

Cited by 52 publications

(52 citation statements)

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“…However, for patients with recurrent asexual parasitemia between day 7 and day 42, 53.57% had patent gametocytemia. The propensity of gametocyte carriage during recurrence is consistent with findings from earlier clinical trials (43). Thus, it is important that therapies for vivax malaria effectively clear both the blood and liver stages, so as to prevent recurrences (recrudescence and relapse), as well as the associated gametocytes.…”

Section: Discussionsupporting

confidence: 75%

Therapeutic Responses of Plasmodium vivax Malaria to Chloroquine and Primaquine Treatment in Northeastern Myanmar

Yuan

Wang

Parker

et al. 2015

Antimicrob Agents Chemother

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h Chloroquine-primaquine (CQ-PQ) continues to be the frontline therapy for radical cure of Plasmodium vivax malaria. Emergence of CQ-resistant (CQR) P. vivax parasites requires a shift to artemisinin combination therapies (ACTs), which imposes a significant financial, logistical, and safety burden. Monitoring the therapeutic efficacy of CQ is thus important. Here, we evaluated the therapeutic efficacy of CQ-PQ for P. vivax malaria in northeast Myanmar. We recruited 587 patients with P. vivax monoinfection attending local malaria clinics during 2012 to 2013. These patients received three daily doses of CQ at a total dose of 24 mg of base/kg of body weight and an 8-day PQ treatment (0.375 mg/kg/day) commencing at the same time as the first CQ dose. Of the 401 patients who finished the 28-day follow-up, the cumulative incidence of recurrent parasitemia was 5.20% (95% confidence interval [CI], 3.04% to 7.36%). Among 361 (61%) patients finishing a 42-day follow-up, the cumulative incidence of recurrent blood-stage infection reached 7.98% (95% CI, 5.20% to 10.76%). The cumulative risk of gametocyte carriage at days 28 and 42 was 2.21% (95% CI, 0.78% to 3.64%) and 3.93% (95% CI, 1.94% to 5.92%), respectively. Interestingly, for all 15 patients with recurrent gametocytemia, this was associated with concurrent asexual stages. Genotyping of recurrent parasites at the merozoite surface protein 3␣ gene locus from 12 patients with recurrent parasitemia within 28 days revealed that 10 of these were the same genotype as at day 0, suggesting recrudescence or relapse. Similar studies in 70 patients in the same area in 2007 showed no recurrent parasitemias within 28 days. The sensitivity to chloroquine of P. vivax in northeastern Myanmar may be deteriorating. Plasmodium vivax has the widest geographical distribution among the four human-infecting species, stretching from the Korean Peninsula to northern Argentina. An estimated 2.48 billion people lived at risk of P. vivax malaria in 2010, of which a large majority was in Central and Southeast Asia (1). Each year, P. vivax infects an estimated 130 to 391 million people (2, 3). Past eradication campaigns have witnessed the resilience of vivax malaria to control efforts. In areas where P. vivax and P. falciparum are coendemic, intensified control efforts have led to major changes in malaria epidemiology, and the problem of vivax malaria has become more prominent (4). With emerging global interests in malaria elimination (5), many nations in which vivax malaria is endemic will inevitably face greater challenges for the control and elimination of this parasite. For example, among the 34 malariaeliminating countries, 26 have malaria burdens mainly or solely due to P. vivax (4).The relative resilience of vivax malaria may be attributed to the formation of dormant hypnozoites in the livers of patients. These hypnozoites awaken in the weeks and months following a primary attack and cause new attacks, called relapses. Thus, treatment of P. vivax malaria requires drugs that target both the ...

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Section: Discussionsupporting

confidence: 75%

Therapeutic Responses of Plasmodium vivax Malaria to Chloroquine and Primaquine Treatment in Northeastern Myanmar

Yuan

Wang

Parker

et al. 2015

Antimicrob Agents Chemother

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“…Detection of gametocytes, through pvs25 gene transcripts, in nearly all qPCR-confirmed P. vivax infections tested is somewhat surprising, since recent studies have found much lower proportions of gametocyte-positive infections in Southeast Asia [47], [48] and Papua New Guinea [49]. Since gametocytes comprise only 2% of circulating blood stages [50], microscopists are likely to miss gametocytes in population-based studies where low-density infections are often sampled [23].…”

Section: Discussionmentioning

confidence: 99%

Epidemiology of Disappearing Plasmodium vivax Malaria: A Case Study in Rural Amazonia

et al. 2014

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BackgroundNew frontier settlements across the Amazon Basin pose a major challenge for malaria elimination in Brazil. Here we describe the epidemiology of malaria during the early phases of occupation of farming settlements in Remansinho area, Brazilian Amazonia. We examine the relative contribution of low-density and asymptomatic parasitemias to the overall Plasmodium vivax burden over a period of declining transmission and discuss potential hurdles for malaria elimination in Remansinho and similar settings.MethodsEight community-wide cross-sectional surveys, involving 584 subjects, were carried out in Remansinho over 3 years and complemented by active and passive surveillance of febrile illnesses between the surveys. We used quantitative PCR to detect low-density asexual parasitemias and gametocytemias missed by conventional microscopy. Mixed-effects multiple logistic regression models were used to characterize independent risk factors for P. vivax infection and disease.Principal Findings/Conclusions P. vivax prevalence decreased from 23.8% (March–April 2010) to 3.0% (April–May 2013), with no P. falciparum infections diagnosed after March–April 2011. Although migrants from malaria-free areas were at increased risk of malaria, their odds of having P. vivax infection and disease decreased by 2–3% with each year of residence in Amazonia. Several findings indicate that low-density and asymptomatic P. vivax parasitemias may complicate residual malaria elimination in Remansinho: (a) the proportion of subpatent infections (i.e. missed by microscopy) increased from 43.8% to 73.1% as P. vivax transmission declined; (b) most (56.6%) P. vivax infections were asymptomatic and 32.8% of them were both subpatent and asymptomatic; (c) asymptomatic parasite carriers accounted for 54.4% of the total P. vivax biomass in the host population; (d) over 90% subpatent and asymptomatic P. vivax had PCR-detectable gametocytemias; and (e) few (17.0%) asymptomatic and subpatent P. vivax infections that were left untreated progressed to clinical disease over 6 weeks of follow-up and became detectable by routine malaria surveillance.

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“…It follows that asymptomatic P. vivax infection is relatively common even in low transmission settings [4]. Additionally, in contrast to P. falciparum gametocytes, P. vivax gametocytes arise early in infection and accompany the majority of symptomatic infections, though they have a relatively short lifespan, on the order of 3 days [32,12]. As with P. falciparum , submicroscopic gametocyte densities have also been shown to lead to mosquito infection [42].…”

Section: The Asymptomatic Reservoir Is Heterogeneous In Terms Of Persmentioning

confidence: 99%

The role of submicroscopic parasitemia in malaria transmission: what is the evidence?

Lin¹,

Saunders²,

Meshnick³

2014

Trends in Parasitology

220

230

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Achieving malaria elimination requires targeting the human reservoir of infection, including those with asymptomatic infection. Smear-positive asymptomatic infections detectable by microscopy are an important reservoir because they often persist for months and harbor gametocytes, the parasite stage infectious to mosquitoes. However, many asymptomatic infections are submicroscopic and can only be detected by molecular methods. While there is some evidence that persons with submicroscopic malaria can infect mosquitoes, transmission is much less likely to occur at submicroscopic gametocyte levels. As malaria elimination programs pursue mass screening and treatment of asymptomatic individuals, further research should strive to define the degree to which submicroscopic malaria contributes to the infectious reservoir, and in turn, what diagnostic detection threshold is needed to effectively interrupt transmission.

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Gametocyte Dynamics and the Role of Drugs in Reducing the Transmission Potential of Plasmodium vivax

Cited by 52 publications

References 50 publications

Therapeutic Responses of Plasmodium vivax Malaria to Chloroquine and Primaquine Treatment in Northeastern Myanmar

Therapeutic Responses of Plasmodium vivax Malaria to Chloroquine and Primaquine Treatment in Northeastern Myanmar

Epidemiology of Disappearing Plasmodium vivax Malaria: A Case Study in Rural Amazonia

The role of submicroscopic parasitemia in malaria transmission: what is the evidence?

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