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Recrudescence, Reinfection, or Relapse? A More Rigorous Framework to Assess Chloroquine Efficacy for Plasmodium vivax Malaria.

ABSTRACT: Background:Plasmodium vivax resistance to chloroquine (CQ) has been reported worldwide, although the World Health Organization clinical drug efficacy studies protocol does not permit classification of patient outcomes. Methods:We enrolled 40 patients with P. vivax malaria in northeastern Cambodia, where >17% treatment failures were previously reported. Patients were treated with CQ (30 mg/kg) and followed for 2 months, with frequent clinical examination and capillary blood sample collection for microscopy, molecular parasite detection and genotyping, and drug concentration measurements. Reinfections were prevented by relocating patients to a transmission-free area. Results:P. vivax parasites were eliminated in all patients by day 3. Genomic analyses revealed that all clones in polyclonal infections were cleared at the same rate, indicating their equal susceptibility to CQ. CQ blood concentrations were below the therapeutic level in all recurrent infections (24 of 40 patients), which were efficiently cleared by a second course of CQ treatment. Genotyping (128 SNPs barcode) and sequences of entire parasite genome (Whole-Genome Sequencing, Illumina) indicated that two thirds (6 of 8) of the recurrent parasites resulted from heterologous relapses whose 50% are from by sibling/recombinant clones. Conclusions:No evidence of CQ resistance was observed. Our data suggest that P. vivax antimalarial drug resistance is likely overestimated and that the current guidelines for clinical drug studies of P. vivax malaria need to be revised.

SUBMITTER: Popovici J

PROVIDER: S-EPMC6306015 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Recrudescence, Reinfection, or Relapse? A More Rigorous Framework to Assess Chloroquine Efficacy for Plasmodium vivax Malaria.

Popovici Jean J Pierce-Friedrich Lindsey L Kim Saorin S Bin Sophalai S Run Vorleak V Lek Dysoley D Hee Kim Hor Daryl KHD Lee Soon-U Lawrence L Cannon Matthew V MV Serre David D Menard Didier D

The Journal of infectious diseases 20190101 2

<h4>Background</h4>Plasmodium vivax resistance to chloroquine (CQ) has been reported worldwide, although the World Health Organization clinical drug efficacy studies protocol does not permit classification of patient outcomes.<h4>Methods</h4>We enrolled 40 patients with P. vivax malaria in northeastern Cambodia, where >17% treatment failures were previously reported. Patients were treated with CQ (30 mg/kg) and followed for 2 months, with frequent clinical examination and capillary blood sample ...[more]

PMID: 30102351

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Project description:Plasmodium vivax has the widest geographic distribution of the human malaria parasites and nearly 2.5 billion people live at risk of infection. The control of P. vivax in individuals and populations is complicated by its ability to relapse weeks to months after initial infection. Strains of P. vivax from different geographical areas are thought to exhibit varied relapse timings. In tropical regions strains relapse quickly (three to six weeks), whereas those in temperate regions do so more slowly (six to twelve months), but no comprehensive assessment of evidence has been conducted. Here observed patterns of relapse periodicity are used to generate predictions of relapse incidence within geographic regions representative of varying parasite transmission.A global review of reports of P. vivax relapse in patients not treated with a radical cure was conducted. Records of time to first P. vivax relapse were positioned by geographic origin relative to expert opinion regions of relapse behaviour and epidemiological zones. Mixed-effects meta-analysis was conducted to determine which geographic classification best described the data, such that a description of the pattern of relapse periodicity within each region could be described. Model outputs of incidence and mean time to relapse were mapped to illustrate the global variation in relapse.Differences in relapse periodicity were best described by a historical geographic classification system used to describe malaria transmission zones based on areas sharing zoological and ecological features. Maps of incidence and time to relapse showed high relapse frequency to be predominant in tropical regions and prolonged relapse in temperate areas.The results indicate that relapse periodicity varies systematically by geographic region and are categorized by nine global regions characterized by similar malaria transmission dynamics. This indicates that relapse may be an adaptation evolved to exploit seasonal changes in vector survival and therefore optimize transmission. Geographic patterns in P. vivax relapse are important to clinicians treating individual infections, epidemiologists trying to infer P. vivax burden, and public health officials trying to control and eliminate the disease in human populations.

Project description:In the present study, we propose and analyze an epidemic mathematical model for malaria dynamics, considering multiple recurrent phenomena: relapse, reinfection, and recrudescence. A limitation in hospital bed capacity, which can affect the treatment rate, is modeled using a saturated treatment function. The qualitative behavior of the model, covering the existence and stability criteria of the endemic equilibrium, is investigated rigorously. The concept of the basic reproduction number of the proposed model is obtained using the concept of the next-generation matrix. We find that the malaria-free equilibrium point is locally asymptotically stable if the basic reproduction number is less than one and unstable if it is larger than one. Our observation on the malaria-endemic equilibrium of the proposed model shows possible multiple endemic equilibria when the basic reproduction number is larger or smaller than one. Hence, we conclude that a condition of a basic reproduction number less than one is not sufficient to guarantee the extinction of malaria from the population. To test our model in a real-life situation, we fit our model parameters using the monthly incidence data from districts in Central Sumba, Indonesia called Wee Luri, which were collected from the Wee Luri Health Center. Using the first twenty months' data from Wee Luri district, we show that our model can fit the data with a confidence interval of 95%. Both analytical and numerical experiments show that a limitation in hospital bed capacity and reinfection can trigger a more substantial possibility of the appearance of backward bifurcation. On the other hand, we find that an increase in relapse can reduce the chance of the appearance of backward bifurcation. A non-trivial result appears in that a higher probability of recrudescence (treatment failure) does not always result in the appearance of backward bifurcation. From the global sensitivity analysis using a combination of Latin hypercube sampling and partial rank correlation coefficient, we found that the initial infection rate in humans and the mosquito infection rate are the most influential parameters in determining the increase in total new human infections. We expand our model as an optimal control problem by including three types of malaria interventions, namely the use of bed net, hospitalization, and fumigation as a time-dependent variable. Using the Pontryagin maximum principle, we characterize our optimal control problem. Results from our cost-effectiveness analysis suggest that hospitalization only is the most cost-effective strategy required to control malaria disease.

Dataset Information

Recrudescence, Reinfection, or Relapse? A More Rigorous Framework to Assess Chloroquine Efficacy for Plasmodium vivax Malaria.

Publications

Recrudescence, Reinfection, or Relapse? A More Rigorous Framework to Assess Chloroquine Efficacy for Plasmodium vivax Malaria.

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