Recrudescence, Reinfection, or Relapse? A More Rigorous Framework to Assess Chloroquine Efficacy for<i>Plasmodium vivax</i>Malaria

Popovici, Jean; Pierce-Friedrich, Lindsey; Kim, Saorin; Bin, Sophalai; Run, Vorleak; Lek, Dysoley; Hee, Kim Hor; Soon-U, Lawrence Lee; Cannon, Matthew; Serre, David; Ménard, Didier

doi:10.1093/infdis/jiy484

Cited by 40 publications

(29 citation statements)

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“…We also included in our analysis, 16 P . vivax isolates collected from recurrences occurring in the 2-months follow up after a standard 3-day course of chloroquine (30 mg/kg) in patients relocated in a non-transmission area [ 45 ].…”

Section: Methodsmentioning

confidence: 99%

Genetic diversity in two Plasmodium vivax protein ligands for reticulocyte invasion

et al. 2018

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The interaction between Plasmodium vivax Duffy binding protein (PvDBP) and Duffy antigen receptor for chemokines (DARC) has been described as critical for the invasion of human reticulocytes, although increasing reports of P. vivax infections in Duffy-negative individuals questions its unique role. To investigate the genetic diversity of the two main protein ligands for reticulocyte invasion, PvDBP and P. vivax Erythrocyte Binding Protein (PvEBP), we analyzed 458 isolates collected in Cambodia and Madagascar from individuals genotyped as Duffy-positive. First, we observed a high proportion of isolates with multiple copies PvEBP from Madagascar (56%) where Duffy negative and positive individuals coexist compared to Cambodia (19%) where Duffy-negative population is virtually absent. Whether the gene amplification observed is responsible for alternate invasion pathways remains to be tested. Second, we found that the PvEBP gene was less diverse than PvDBP gene (12 vs. 33 alleles) but provided evidence for an excess of nonsynonymous mutations with the complete absence of synonymous mutations. This finding reveals that PvEBP is under strong diversifying selection, and confirms the importance of this protein ligand in the invasion process of the human reticulocytes and as a target of acquired immunity. These observations highlight how genomic changes in parasite ligands improve the fitness of P. vivax isolates in the face of immune pressure and receptor polymorphisms.

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Section: Methodsmentioning

confidence: 99%

Genetic diversity in two Plasmodium vivax protein ligands for reticulocyte invasion

et al. 2018

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“…the primary infection could be A1B3 and A2B4, and the recurrence could be A1B4 and A2B3). Parasites that are siblings, and also the infections that they cause, could be deemed homologous (as in [6]), heterologous (as in [26,28]), or referred to separately (as in [18,65,83]).…”

Section: Terminology: Homologous and Heterologousmentioning

confidence: 99%

“…primaquine, the only radical cure currently available, and tafenoquine, approved in some countries but yet to be deployed in endemic areas) in populations at continued risk of infection will be biased downwards by the background transmission rate. Finally, the inability to distinguish between relapse and recrudescence (recurrence of the blood-stage infection as result of blood-stage treatment failure) means that it is difficult to estimate the curative efficacy of a blood-stage treatment in endemic areas [28]. This contrasts with Plasmodium falciparum malaria where standardised genotyping is used effectively to distinguish recrudescence from reinfection, allowing for the adjustment of efficacy estimates in populations at continued risk of reinfection [29-31].…”

Section: Introductionmentioning

confidence: 99%

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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“…Distinguishing relapses from reinfections is complex, since hypnozoites causing a relapse may be genetically different from the parasites that caused the initial infection [ 74 ]. Recent studies using whole genome sequencing data have demonstrated the utility of molecular data to identify recurrent infections that are genetically different from day-zero parasites, but appear to be related, sharing identity by descent [ 75 , 76 ]. Pairs of day-zero and recurrent parasites that are genetically related are more likely to have derived from the same mosquito bite than from different inoculations (as in a reinfection) and are, therefore, more likely to represent relapse rather than re-infection events.…”

Section: Introductionmentioning

confidence: 99%

Implementing parasite genotyping into national surveillance frameworks: feedback from control programmes and researchers in the Asia–Pacific region

Noviyanti

Miotto

Barry

et al. 2020

Malar J

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The Asia–Pacific region faces formidable challenges in achieving malaria elimination by the proposed target in 2030. Molecular surveillance of Plasmodium parasites can provide important information on malaria transmission and adaptation, which can inform national malaria control programmes (NMCPs) in decision-making processes. In November 2019 a parasite genotyping workshop was held in Jakarta, Indonesia, to review molecular approaches for parasite surveillance and explore ways in which these tools can be integrated into public health systems and inform policy. The meeting was attended by 70 participants from 8 malaria-endemic countries and partners of the Asia Pacific Malaria Elimination Network. The participants acknowledged the utility of multiple use cases for parasite genotyping including: quantifying the prevalence of drug resistant parasites, predicting risks of treatment failure, identifying major routes and reservoirs of infection, monitoring imported malaria and its contribution to local transmission, characterizing the origins and dynamics of malaria outbreaks, and estimating the frequency of Plasmodium vivax relapses. However, the priority of each use case varies with different endemic settings. Although a one-size-fits-all approach to molecular surveillance is unlikely to be applicable across the Asia–Pacific region, consensus on the spectrum of added-value activities will help support data sharing across national boundaries. Knowledge exchange is needed to establish local expertise in different laboratory-based methodologies and bioinformatics processes. Collaborative research involving local and international teams will help maximize the impact of analytical outputs on the operational needs of NMCPs. Research is also needed to explore the cost-effectiveness of genetic epidemiology for different use cases to help to leverage funding for wide-scale implementation. Engagement between NMCPs and local researchers will be critical throughout this process.

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Recrudescence, Reinfection, or Relapse? A More Rigorous Framework to Assess Chloroquine Efficacy forPlasmodium vivaxMalaria

Abstract: No evidence of chloroquine resistance were observed. Our data suggest that P. vivax antimalarial drug resistance is likely overestimated and that the current guidelines for clinical drug studies in vivax malaria need to be revised.

Cited by 40 publications

References 30 publications

Genetic diversity in two Plasmodium vivax protein ligands for reticulocyte invasion

Genetic diversity in two Plasmodium vivax protein ligands for reticulocyte invasion

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

Implementing parasite genotyping into national surveillance frameworks: feedback from control programmes and researchers in the Asia–Pacific region

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