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      Resolving the cause of recurrent Plasmodium vivax malaria probabilistically

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          Abstract

          Relapses arising from dormant liver-stage Plasmodium vivax parasites (hypnozoites) are a major cause of vivax malaria. However, in endemic areas, a recurrent blood-stage infection following treatment can be hypnozoite-derived (relapse), a blood-stage treatment failure (recrudescence), or a newly acquired infection (reinfection). Each of these requires a different prevention strategy, but it was not previously possible to distinguish between them reliably. We show that individual vivax malaria recurrences can be characterised probabilistically by combined modelling of time-to-event and genetic data within a framework incorporating identity-by-descent. Analysis of pooled patient data on 1441 recurrent P. vivax infections in 1299 patients on the Thailand–Myanmar border observed over 1000 patient follow-up years shows that, without primaquine radical curative treatment, 3 in 4 patients relapse. In contrast, after supervised high-dose primaquine only 1 in 40 relapse. In this region of frequent relapsing P. vivax, failure rates after supervised high-dose primaquine are significantly lower (∼3%) than estimated previously.

          Abstract

          Relapse, reinfection and recrudescence can all cause recurrent infection after treatment of Plasmodium vivax malaria in endemic areas, but are difficult to distinguish. Here the authors show that they can be differentiated probabilistically and thereby demonstrate the high efficacy of primaquine treatment in preventing relapse.

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          Most cited references 39

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          Determinants of relapse periodicity in Plasmodium vivax malaria

          Plasmodium vivax is a major cause of febrile illness in endemic areas of Asia, Central and South America, and the horn of Africa. Plasmodium vivax infections are characterized by relapses of malaria arising from persistent liver stages of the parasite (hypnozoites) which can be prevented only by 8-aminoquinoline anti-malarials. Tropical P. vivax relapses at three week intervals if rapidly eliminated anti-malarials are given for treatment, whereas in temperate regions and parts of the sub-tropics P. vivax infections are characterized either by a long incubation or a long-latency period between illness and relapse - in both cases approximating 8-10 months. The epidemiology of the different relapse phenotypes has not been defined adequately despite obvious relevance to malaria control and elimination. The number of sporozoites inoculated by the anopheline mosquito is an important determinant of both the timing and the number of relapses. The intervals between relapses display a remarkable periodicity which has not been explained. Evidence is presented that the proportion of patients who have successive relapses is relatively constant and that the factor which activates hypnozoites and leads to regular interval relapse in vivax malaria is the systemic febrile illness itself. It is proposed that in endemic areas a large proportion of the population harbours latent hypnozoites which can be activated by a systemic illness such as vivax or falciparum malaria. This explains the high rates of vivax following falciparum malaria, the high proportion of heterologous genotypes in relapses, the higher rates of relapse in people living in endemic areas compared with artificial infection studies, and, by facilitating recombination between different genotypes, contributes to P. vivax genetic diversity particularly in low transmission settings. Long-latency P. vivax phenotypes may be more widespread and more prevalent than currently thought. These observations have important implications for the assessment of radical treatment efficacy and for malaria control and elimination.
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            Relapses of Plasmodium vivax infection usually result from activation of heterologous hypnozoites.

            Relapses originating from hypnozoites are characteristic of Plasmodium vivax infections. Thus, reappearance of parasitemia after treatment can result from relapse, recrudescence, or reinfection. It has been assumed that parasites causing relapse would be a subset of the parasites that caused the primary infection. Paired samples were collected before initiation of antimalarial treatment and at recurrence of parasitemia from 149 patients with vivax malaria in Thailand (n=36), where reinfection could be excluded, and during field studies in Myanmar (n=75) and India (n=38). Combined genetic data from 2 genotyping approaches showed that novel P. vivax populations were present in the majority of patients with recurrent infection (107 [72%] of 149 patients overall [78% of patients in Thailand, 75% of patients in Myanmar {Burma}, and 63% of patients in India]). In 61% of the Thai and Burmese patients and in 55% of the Indian patients, the recurrent infections contained none of the parasite genotypes that caused the acute infection. The P. vivax populations emerging from hypnozoites commonly differ from the populations that caused the acute episode. Activation of heterologous hypnozoite populations is the most common cause of first relapse in patients with vivax malaria.
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              Global Epidemiology of Plasmodium vivax

              Plasmodium vivax is the most widespread human malaria, putting 2.5 billion people at risk of infection. Its unique biological and epidemiological characteristics pose challenges to control strategies that have been principally targeted against Plasmodium falciparum. Unlike P. falciparum, P. vivax infections have typically low blood-stage parasitemia with gametocytes emerging before illness manifests, and dormant liver stages causing relapses. These traits affect both its geographic distribution and transmission patterns. Asymptomatic infections, high-risk groups, and resulting case burdens are described in this review. Despite relatively low prevalence measurements and parasitemia levels, along with high proportions of asymptomatic cases, this parasite is not benign. Plasmodium vivax can be associated with severe and even fatal illness. Spreading resistance to chloroquine against the acute attack, and the operational inadequacy of primaquine against the multiple attacks of relapse, exacerbates the risk of poor outcomes among the tens of millions suffering from infection each year. Without strategies accounting for these P. vivax-specific characteristics, progress toward elimination of endemic malaria transmission will be substantially impeded.
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                Author and article information

                Contributors
                ataylor@hsph.harvard.edu
                jwatowatson@gmail.com
                nickwdt@tropmedres.ac
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                6 December 2019
                6 December 2019
                2019
                : 10
                Affiliations
                [1 ]ISNI 000000041936754X, GRID grid.38142.3c, Center for Communicable Disease Dynamics, Department of Epidemiology, , Harvard T. H. Chan School of Public Health, ; Boston, MA 02115 USA
                [2 ]GRID grid.66859.34, Broad Institute of MIT and Harvard, ; Cambridge, MA 02142 USA
                [3 ]ISNI 0000 0004 1937 0490, GRID grid.10223.32, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, , Mahidol University, ; Bangkok, 10400 Thailand
                [4 ]ISNI 0000 0004 1936 8948, GRID grid.4991.5, Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, , University of Oxford, ; Oxford, OX3 7FZ UK
                [5 ]ISNI 0000 0004 1937 0490, GRID grid.10223.32, Shoklo Malaria Research Unit, ; Mae Sot, Tak Province 63110 Thailand
                [6 ]ISNI 0000 0004 1937 0490, GRID grid.10223.32, Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, , Mahidol University, ; Bangkok, 10400 Thailand
                [7 ]ISNI 000000041936754X, GRID grid.38142.3c, Department of Immunology and Infectious Diseases, , Harvard T. H. Chan School of Public Health, ; Boston, MA 02115 USA
                Article
                13412
                10.1038/s41467-019-13412-x
                6898227
                31811128
                ab9c3b5d-d0be-454b-a510-a177a5c7f8b6
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: FundRef https://doi.org/10.13039/100000057, U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS);
                Award ID: R35GM12471502
                Award ID: R35GM12471502
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100004396, Thailand Research Fund (TRF);
                Award ID: PHD/0032/2556
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000060, U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID);
                Award ID: U19AI110818
                Award Recipient :
                Funded by: U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
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                © The Author(s) 2019

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                population genetics, malaria, epidemiology, statistics

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