Chloroquine Versus Dihydroartemisinin-Piperaquine With Standard High-dose Primaquine Given Either for 7 Days or 14 Days in Plasmodium vivax Malaria

Chu, Cindy S.; Phyo, Aung Pyae; Turner, Claudia; Win, Htun Htun; Poe, Naw Pet; Yotyingaphiram, Widi; Thinraow, Suradet; Wilairisak, Pornpimon; Raksapraidee, Rattanaporn; Carrara, Verena I.; Paw, Moo Kho; Wiladphaingern, Jacher; Proux, Stéphane; Bancone, Germana; Sriprawat, Kanlaya; Lee, Sue J.; Jeeyapant, Atthanee; Watson, James A; Tärning, Joel; Imwong, Mallika; Nosten, François; White, Nicholas J.

doi:10.1093/cid/ciy735

Cited by 60 publications

(104 citation statements)

References 28 publications

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“…Distances, ρ and k feature in the HMM only. two clinical trails on the Thailand-Myanmar border [55,56]. The data were genotyped at three to nine highly polyallelic microsatellites (MS).…”

Section: Plasmodium Datamentioning

confidence: 99%

Estimating relatedness between malaria parasites

Taylor

Jacob

Neafsey

et al. 2019

Preprint

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Understanding the relatedness of individuals within or between populations is a common goal in biology. Increasingly, relatedness features in genetic epidemiology studies of pathogens. These studies are relatively new compared to those in humans and other organisms, but are important for designing interventions and understanding pathogen transmission. Only recently have researchers begun to routinely apply relatedness to apicomplexan eukaryotic malaria parasites, and to date have used a range of different approaches on an ad hoc basis. It remains unclear how to compare different studies, therefore, and which measures to use. Here, we systematically compare measures based on identity-by-state and identity-by-descent using a globally diverse data set of malaria parasites, Plasmodium falciparum and Plasmodium vivax, and provide marker requirements for estimates based on identity-by-descent. We formally show that the informativeness of polyallelic markers for relatedness inference is maximised when alleles are equifrequent. Estimates based on identity-bystate are sensitive to allele frequencies, which vary across populations and by experimental design. For portability across studies, we thus recommend estimates based on identity-by-descent. To generate reliable estimates, we recommend approximately 200 biallelic or 100 polyallelic markers. Confidence intervals illuminate inference across studies based on different sets of markers. These marker requirements, unlike many thus far reported, are immediately applicable to haploid malaria parasites and other haploid eukaryotes. This is the first attempt to provide rigorous analysis of the reliability of, and requirements for, relatedness inference in malaria genetic epidemiology, and will provide a basis for statistically informed prospective study design and surveillance strategies.

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“…Distances, ρ and k feature in the HMM only. two clinical trails on the Thailand-Myanmar border [55,56]. The data were genotyped at three to nine highly polyallelic microsatellites (MS).…”

Section: Plasmodium Datamentioning

confidence: 99%

Estimating relatedness between malaria parasites

Taylor

Jacob

Neafsey

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…In the VHX study patients of all ages were randomised to receive either artesunate, chloroquine or chloroquine and primaquine [4]. In the BPD study patients were randomised first to receive either chloroquine or dihydroartemisinin-piperaquine and second to receive either 14 days of primaquine 0.5mg/kg/day or 7 days of primaquine 1mg/kg/day [32]. All doses were supervised in both studies.…”

Section: Resultsmentioning

confidence: 99%

“…These estimates of the radical curative efficacy of high-dose primaquine used all available data from the 655 individuals enrolled in the BPD study, which had requisite genetic data for all but 5 of 92 recurrences. This reinfection adjusted estimate is a considerable reduction from the original reinfection unadjusted estimate of the failure rate at 12% (80% CI: 10-14) [32].…”

Section: Resultsmentioning

confidence: 99%

“…The most important operationally relevant result from this analysis is a re-evaluation of the estimated radical cure failure rate following high-dose primaquine. We re-estimated the true failure rate in the BPD study to be 2.6% as compared to the published reinfection unadjusted estimate of 12% [32]. The radical curative efficacy of primaquine is not a fixed property - even when reinfections are discounted, it depends on hypnozoite burden and thus the background level of transmission [6, 34] - so these results also probably reflect recent improvements in malaria control in the area [36].…”

Section: Discussionmentioning

confidence: 99%

“…This section summarizes the clinical procedures followed in the Vivax History (VHX) trial [4] and the Best Primaquine Dose (BPD) trial [32]. Both trials were conducted by the Shoklo Malaria Research Unit in clinics along the Thailand-Myanmar border in northwestern Thailand.…”

Section: Methodsmentioning

confidence: 99%

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Estimating the probable cause of recurrence in Plasmodium vivax malaria: relapse, reinfection or recrudescence?

Watson

et al. 2018

Preprint

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BackgroundRelapse of Plasmodium vivax infection is the main cause of vivax malaria in many parts of Asia. However at the individual patient level, recurrence of a blood stage infection following treatment within the endemic area can be either a relapse (from dormant liver-stage parasites), a recrudescence (blood-stage treatment failure), or a reinfection (following a new mosquito inoculation). Each requires a different prevention strategy, but previously they could not be distinguished reliably. Time-of-event and genetic data provide complimentary information about the cause of P. vivax recurrence, but the optimum approach to genotyping and analysis remains uncertain. MethodsIndividual-level data from two large drug trials in acute vivax malaria patients (Vivax History: VHX; Best Primaquine Dose: BPD) conducted on the Thailand-Myanmar border with follow-up of one year were pooled (n=1299). A total of 710 isolates from both acute and recurrent P. vivax episodes were genotyped using 3-9 highly polymorphic microsatellite markers. These pooled data were analyzed using a novel population statistical model incorporating an assessment of genetic relatedness, treatment drug administered, and the time-to-recurrence. Results99% of genotyped recurrences in individuals who did not receive primaquine (n=365) were estimated to be relapses. In comparison, 14% of genotyped recurrences (n=121) were estimated to be relapses following high-dose supervised primaquine. By comparing episodes across individuals (90194 comparisons), the false-positive rate of relapse December 23, 2018 1/43 identification using genetic data alone was estimated to be 2.2%. We estimated the true failure rate after high-dose primaquine (7mg/kg total dose) to be 2.6% in this epidemiological context, substantially lower the reinfection unadjusted estimate of 12%. Simulation studies show that 9 highly polymorphic microsatellite markers suffice to discriminate between recurrence states. Drug exposures reflected by plasma carboxy-primaquine concentrations were not predictive of treatment failure, but did identify non-adherence. ConclusionUsing this novel statistical model, relapse of P. vivax malaria could be distinguished reliably from reinfection. This showed that in this population supervised high-dose primaquine could avert up to 99% of relapses. In low transmission settings, microsatellite genotyping combined with time-to-event data can accurately discriminate between the different causes of recurrent P. vivax malaria. Author summaryOne hundred years ago, Plasmodium vivax, the most globally diverse cause of human malaria, was present across most of the old-world, throughout tropical and temperate climes. Its main evolutionary advantage over Plasmodium falciparum, responsible for the most deadly type of human malaria, is its ability to stay dormant in the liver, emerging weeks to years later causing recurring illness and continuing transmission. The dormant liver-stage parasites are called hypnozoites. A recurrent infection can either be hypnozoite-derived (...

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