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Background There is a high risk of Plasmodium vivax parasitaemia following treatment of falciparum malaria. Our study aimed to quantify this risk and the associated determinants using an individual patient data meta-analysis in order to identify populations in which a policy of universal radical cure, combining artemisinin-based combination therapy (ACT) with a hypnozoitocidal antimalarial drug, would be beneficial. Methods and findings A systematic review of Medline, Embase, Web of Science, and the Cochrane Database of Systematic Reviews identified efficacy studies of uncomplicated falciparum malaria treated with ACT that were undertaken in regions coendemic for P. vivax between 1 January 1960 and 5 January 2018. Data from eligible studies were pooled using standardised methodology. The risk of P. vivax parasitaemia at days 42 and 63 and associated risk factors were investigated by multivariable Cox regression analyses. Study quality was assessed using a tool developed by the Joanna Briggs Institute. The study was registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42018097400). In total, 42 studies enrolling 15,341 patients were included in the analysis, including 30 randomised controlled trials and 12 cohort studies. Overall, 14,146 (92.2%) patients had P. falciparum monoinfection and 1,195 (7.8%) mixed infection with P. falciparum and P. vivax. The median age was 17.0 years (interquartile range [IQR] = 9.0-29.0 years; range = 0-80 years), with 1,584 (10.3%) patients younger than 5 years. 2,711 (17.7%) patients were treated with artemether-lumefantrine (AL, 13 studies), 651 (4.2%) with artesunate-amodiaquine (AA, 6 studies), 7,340 (47.8%) with artesunate-mefloquine (AM, 25 studies), and 4,639 (30.2%) with dihydroartemisinin-piperaquine (DP, 16 studies). 14,537 patients (94.8%) were enrolled from the Asia-Pacific region, 684 (4.5%) from the Americas, and 120 (0.8%) from Africa. At day 42, the cumulative risk of vivax parasitaemia following treatment of P. falciparum was 31.1% (95% CI 28.9-33.4) after AL, 14.1% (95% CI 10.8-18.3) after AA, 7.4% (95% CI 6.7-8.1) after AM, and 4.5% (95% CI 3.9-5.3) after DP. By day 63, the risks had risen to 39.9% (95% CI 36.6-43.3), 42.4% (95% CI 34.7-51.2), 22.8% (95% CI 21.2-24.4), and 12.8% (95% CI 11.4-14.5), respectively. In multivariable analyses, the highest rate of P. vivax parasitaemia over 42 days of follow-up was in patients residing in areas of short relapse periodicity (adjusted hazard ratio [AHR] = 6.2, 95% CI 2.0-19.5; p = 0.002); patients treated with AL (AHR = 6.2, 95% CI 4.6-8.5; p < 0.001), AA (AHR = 2.3, 95% CI 1.4-3.7; p = 0.001), or AM (AHR = 1.4, 95% CI 1.0-1.9; p = 0.028) compared with DP; and patients who did not clear their initial parasitaemia within 2 days (AHR = 1.8, 95% CI 1.4-2.3; p < 0.001). The analysis was limited by heterogeneity between study populations and lack of data from very low transmission settings. Study quality was high. Conclusions In this meta-analysis, we found a high risk of P. vivax parasitaemia after treatment of P. falciparum malaria that varied significantly between studies. These P. vivax infections are likely attributable to relapses that could be prevented with radical cure including a hypnozoitocidal agent; however, the benefits of such a novel strategy will vary considerably between geographical areas., Author(s): Mohammad S. Hossain 1,2,3,4, Robert J. Commons 1,2,5, Nicholas M. Douglas 2,3, Kamala Thriemer 2, Bereket H. Alemayehu 6, Chanaki Amaratunga 7, Anupkumar R. Anvikar 8, Elizabeth A. Ashley [...]

Background: Plasmodium vivax is a neglected human malaria parasite that causes significant morbidity in the Americas, the Middle East, Asia, and the Western Pacific. Population genomic approaches remain little explored to map local and regional transmission pathways of P. vivax across the main endemic sites in the Americas, where great progress has been made towards malaria elimination over the past decades. Methodology/Principal findings: We analyze 38 patient-derived P. vivax genome sequences from Mâncio Lima (ML)–the Amazonian malaria hotspot next to the Brazil-Peru border—and 24 sequences from two other sites in Acre State, Brazil, a country that contributes 23% of malaria cases in the Americas. We show that the P. vivax population of ML is genetically diverse (π = 4.7 × 10−4), with a high polymorphism particularly in genes encoding proteins putatively involved in red blood cell invasion. Paradoxically, however, parasites display strong genome-wide linkage disequilibrium, being fragmented into discrete lineages that are remarkably stable across time and space, with only occasional recombination between them. Using identity-by-descent approaches, we identified a large cluster of closely related sequences that comprises 16 of 38 genomes sampled in ML over 26 months. Importantly, we found significant ancestry sharing between parasites at a large geographic distance, consistent with substantial gene flow between regional P. vivax populations. Conclusions/Significance: We have characterized the sustained expansion of highly inbred P. vivax lineages in a malaria hotspot that can seed regional transmission. Potential source populations in hotspots represent a priority target for malaria elimination in the Amazon. Authors' summary: Plasmodium vivax is the geographically most widespread human malaria parasite and causes 80% of the malaria burden in the Americas. Here we use whole-genome sequencing to explore levels of parasite relatedness and infer P. vivax transmission networks in the upper Juruá Valley, the main transmission hotspot in Amazonian Brazil. We characterize a genetically diverse population that displays significant linkage disequilibrium, consistent with the local circulation of highly inbred but genetically distant parasite lineages. Noteworthy, these discrete lineages remain stable over time and share recent ancestry with parasites at a large geographic distance. These results illustrate the power of genomic epidemiology approaches to map potential source parasite populations and prioritize areas for targeted control interventions to eliminate residual P. vivax transmission in the Amazon and similar endemic settings worldwide. [ABSTRACT FROM AUTHOR]

We investigated linear growth and weight attained among 772 children at 10–15 months of age in the first population-based birth cohort in the Brazilian Amazon. Sociodemographic, maternal and birth characteristics were collected in interviews soon after birth at baseline. Anthropometric evaluation was conducted at 10–15 months. Multiple linear regression models were fitted for length-for-age (LAZ) and body mass index (BMI)-for-age Z scores (BAZ), considering a hierarchical conceptual framework with determinants at distal, intermediate and proximal levels, with adjustment for the child’s sex and age. Mean LAZ and BAZ were 0.31 (SD: 1.13) and 0.35 (SD: 1.06), respectively. Overall, 2.2% of children were stunted and 6.6% overweight. Among socioeconomic factors, household wealth index was positively associated with LAZ (p for trend = 0.01), while children whose families received assistance from the Bolsa Família conditional cash transfer program were 0.16 Z score thinner (95% CI: -0.31, -0.00). Maternal height and BMI were positively associated with both LAZ and BAZ at 10–15 months of age (p for trend <0.001). Child’s size at birth was positively related with LAZ (p<0.001 for both birth weight and length). BAZ was 0.34 (95% CI: 0.24, 0.44) higher, but 0.11 lower (95% CI: -0.21, -0.02), for each increase in 1 Z score of birth weight and length, respectively. Children with at least one reported malaria episode within the first year of life were 0.58 (95% CI: -1.05, -0.11) Z score shorter. Socioeconomic and intergenerational factors were consistently associated with LAZ and BAZ at 10–15 months of age. The occurrence of malaria was detrimental to linear growth. In a malaria endemic region, reduction of inequalities and disease burden over the first 1,000 days of life is essential for taking advantage of a critical window of opportunity that can redirect child growth trajectories toward better health and nutrition conditions in the long term. [ABSTRACT FROM AUTHOR]