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      Epidemiology of Plasmodium vivax Malaria in Peru

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          Abstract

          Malaria in Peru, dominated by Plasmodium vivax, remains a public health problem. The 1990s saw newly epidemic malaria emerge, primarily in the Loreto Department in the Amazon region, including areas near to Iquitos, the capital city, but sporadic malaria transmission also occurred in the 1990s–2000s in both north-coastal Peru and the gold mining regions of southeastern Peru. Although a Global Fund-supported intervention (PAMAFRO, 2005–2010) was temporally associated with a decrease of malaria transmission, from 2012 to the present, both P. vivax and Plasmodium falciparum malaria cases have rapidly increased. The Peruvian Ministry of Health continues to provide artemesinin-based combination therapy for microscopy-confirmed cases of P. falciparum and chloroquine–primaquine for P. vivax. Malaria transmission continues in remote areas nonetheless, where the mobility of humans and parasites facilitates continued reintroduction outside of ongoing surveillance activities, which is critical to address for future malaria control and elimination efforts. Ongoing P. vivax research gaps in Peru include the following: identification of asymptomatic parasitemics, quantification of the contribution of patent and subpatent parasitemics to mosquito transmission, diagnosis of nonparasitemic hypnozoite carriers, and implementation of surveillance for potential emergence of chloroquine- and 8-aminoquinoline-resistant P. vivax. Clinical trials of tafenoquine in Peru have been promising, and glucose-6-phosphate dehydrogenase deficiency in the region has not been observed to be a limitation to its use. Larger-scale challenges for P. vivax (and malaria in general) in Peru include logistical difficulties in accessing remote riverine populations, consequences of government policy and poverty trends, and obtaining international funding for malaria control and elimination.

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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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            New developments in Plasmodium vivax malaria: severe disease and the rise of chloroquine resistance.

            Unlike Plasmodium falciparum, Plasmodium vivax rarely causes severe disease in healthy travellers or in temperate endemic regions and has been regarded as readily treatable with chloroquine. However, in tropical areas, recent reports have highlighted severe and fatal disease associated with P. vivax infection. We review the evidence for severe disease and the spread of drug-resistant P. vivax and speculate how these maybe related. Studies from Indonesia, Papua New Guinea, Thailand and India have shown that 21-27% of patients with severe malaria have P. vivax monoinfection. The clinical spectrum of these cases is broad with an overall mortality of 0.8-1.6%. Major manifestations include severe anaemia and respiratory distress, with infants being particularly vulnerable. Most reports of severe and fatal vivax malaria come from endemic regions where populations have limited access to healthcare, a high prevalence of comorbidity and where drug-resistant P. vivax strains and partially effective primaquine regimens significantly undermine the radical cure and control of this relapsing infection. The mechanisms underlying severe disease in vivax malaria remain poorly defined. Severe, fatal and multidrug-resistant vivax malaria challenge our perception of P. vivax as a benign disease. Strategies to understand and address these phenomena are needed urgently if the global elimination of malaria is to succeed.
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              Tafenoquine plus chloroquine for the treatment and relapse prevention of Plasmodium vivax malaria (DETECTIVE): a multicentre, double-blind, randomised, phase 2b dose-selection study.

              Clinical effectiveness of previous regimens to treat Plasmodium vivax infection have been hampered by compliance. We aimed to assess the dose-response, safety, and tolerability of single-dose tafenoquine plus 3-day chloroquine for P vivax malaria radical cure. In this double-blind, randomised, dose-ranging phase 2b study, men and women (aged ≥16 years) with microscopically confirmed P vivax monoinfection (parasite density >100 to 7500 per μL blood). The primary efficacy endpoint was relapse-free efficacy at 6 months from initial dose (ie, clearance of initial infection without subsequent microscopically confirmed infection), analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01376167. Between Sept 19, 2011, and March 25, 2013, 329 patients were randomly assigned to a treatment group (chloroquine plus tafenoquine 50 mg [n=55], 100 mg [n=57], 300 mg [n=57], 600 mg [n=56]; or to chloroquine plus primaquine [n=50]; or chloroquine alone [n=54]). Relapse-free efficacy at 6 months was 57·7% (95% CI 43-70) with tafenoquine 50 mg, 54·1% (40-66) with tafenoquine 100 mg, 89·2% (77-95) with tafenoquine 300 mg, 91·9% (80-97) with tafenoquine 600 mg, 77·3% (63-87) with primaquine, and 37·5% (23-52) with chloroquine alone. Tafenoquine 300 mg and 600 mg had better efficacy than chloroquine alone (treatment differences 51·7% [95% CI 35-69], p<0·0001, with tafenoquine 300 mg and 54·5% [38-71], p<0·0001, with tafenoquine 600 mg), as did primaquine (treatment difference 39·9% [21-59], p=0·0004). Adverse events were similar between treatments. 29 serious adverse events occurred in 26 (8%) of 329 patients; QT prolongation was the most common serious adverse event (11 [3%] of 329), occurring in five (2%) of 225 patients receiving tafenoquine, four (8%) of 50 patients receiving primaquine, and two (4%) of 54 patients receiving chloroquine alone, with no evidence of an additional effect on QT of chloroquine plus tafenoquine coadministration. Single-dose tafenoquine 300 mg coadministered with chloroquine for P vivax malaria relapse prevention was more efficacious than chloroquine alone, with a similar safety profile. As a result, it has been selected for further clinical assessment in phase 3. GlaxoSmithKline, Medicines for Malaria Venture. Copyright © 2014 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Am J Trop Med Hyg
                Am. J. Trop. Med. Hyg
                tpmd
                The American Journal of Tropical Medicine and Hygiene
                The American Society of Tropical Medicine and Hygiene
                0002-9637
                1476-1645
                28 December 2016
                28 December 2016
                : 95
                : 6 Suppl , Control and Elimination of Plasmodium vivax Malaria: The Evidence Base
                : 133-144
                Affiliations
                [1 ]Instituto de Medicina Tropical “Alexander von Humboldt,” Universidad Peruana Cayetano Heredia, Lima, Peru.
                [2 ]Research Institute of Health and Society, Université Catholique de Louvain, Brussels, Belgium.
                [3 ]Departamento de Ciencias Celulares y Moleculares, Facultad de Ciencias y Filosofia, Universidad Peruana Cayetano Heredia, Lima, Peru.
                [4 ]Department of Biomedical Sciences, School of Public Health, University at Albany (State University of New York), Albany, New York.
                [5 ]Wadsworth Center, New York State Department of Health, Albany, New York.
                [6 ]Division of Infectious Diseases, Department of Medicine, University of California San Diego, San Diego, California.
                [7 ]Facultad de Salud Pública, Universidad Peruana Cayetano Heredia, Lima, Peru.
                [8 ]Dirección Regional de Salud Loreto, Ministerio de Salud, Iquitos, Peru.
                Author notes
                * Address correspondence to Joseph M. Vinetz, University of California San Diego, MC0760, 9500 Gilman Drive, La Jolla, CA 92093, and Instituto de Medicina Tropical “Alexander von Humboldt,” Universidad Peruana Cayetano Heredia, Avenida Honório Delgado 430, Lima, Peru. E-mails: jvinetz@ 123456ucsd.edu or joseph.vinetz@ 123456upch.pe
                Article
                10.4269/ajtmh.16-0268
                5201219
                27799639
                e4dea8a7-d02d-4982-ad13-5f22d22e80ef
                © The American Society of Tropical Medicine and Hygiene

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 06 April 2016
                : 29 September 2016
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                Infectious disease & Microbiology
                Infectious disease & Microbiology

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