title: Filling gaps on ivermectin knowledge: effects on the survival and reproduction of Anopheles aquasalis, a Latin American malaria vector.
abstract: BACKGROUND
  Strategies designed to advance towards malaria elimination rely on the detection and treatment of infections, rather than fever, and the interruption of malaria transmission between mosquitoes and humans. Mass drug administration with anti-malarials directed at eliminating parasites in blood, either to entire populations or targeting only those with malaria infections, are considered useful strategies to progress towards malaria elimination, but may be insufficient if applied on their own. These strategies assume a closer contact with populations, so incorporating a vector control intervention tool to those approaches could significantly enhance their efficacy. Ivermectin, an endectocide drug efficacious against a range of Anopheles species, could be added to other drug-based interventions. Interestingly, ivermectin could also be useful to target outdoor feeding and resting vectors, something not possible with current vector control tools, such as impregnated bed nets or indoor residual spraying (IRS).
  
  
  RESULTS
  Anopheles aquasalis susceptibility to ivermectin was assessed. In vivo assessments were performed in six volunteers, being three men and three women. The effect of ivermectin on reproductive fitness and mosquito survivorship using membrane feeding assay (MFA) and direct feeding assay (DFA) was assessed and compared. The ivermectin lethal concentration (LC) values were LC50= 47.03 ng/ml [44.68-49.40], LC25= 31.92 ng/ml [28.60-34.57] and LC5= 18.28 ng/ml [14.51-21.45]. Ivermectin significantly reduced the survivorship of An. aquasalis blood-fed 4 h post-ingestion (X2[N = 880] = 328.16, p < 0.001), 2 days post-ingestion (DPI 2) (X2[N = 983] = 156.75, p < 0.001), DPI 7 (X2[N = 935] = 31.17, p < 0.001) and DPI 14 (X2[N = 898] = 38.63, p < 0.001) compared to the blood fed on the untreated control. The average number of oviposited eggs per female was significantly lower in LC5group (22.44 [SD = 3.38]) than in control (34.70 [SD = 12.09]) (X2[N = 199] = 10.52, p < 0.001) as well as the egg hatch rate (LC5= 74.76 [SD = 5.48]) (Control = 81.91 [SD = 5.92]) (X2[N = 124] = 64.24, p < 0.001). However, no differences were observed on the number of pupae that developed from larvae (Control = 34.19 [SD = 10.42) and group (LC5= 33.33 [SD = 11.97]) (X2[N = 124] = 0.96, p > 0.05).
  
  
  CONCLUSIONS
  Ivermectin drug reduces mosquito survivorship when blood fed on volunteer blood from 4 h to 14 days post-ingestion controlling for volunteers' gender. Ivermectin at mosquito sub-lethal concentrations (LC5) reduces fecundity and egg hatch rate but not the number of pupae that developed from larvae. DFA had significantly higher effects on mosquito survival compared to MFA. The findings are presented and discussed through the prism of malaria elimination in the Amazon region.
authors.affiliation: Diretoria de Ensino e Pesquisa, Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, Brazil. vandersons@gmail.com.|Escola Superior de Ciências da Saúde, Universidade do Estado do Amazonas, Manaus, Brazil. vandersons@gmail.com.|Sala de Análise de Situação em Saúde, Fundação de Vigilância em Saúde do Amazonas, Manaus, Brazil. vandersons@gmail.com.
authors.forename: Vanderson S
authors.initials: VS
authors.lastname: Sampaio
authors.affiliation: Diretoria de Ensino e Pesquisa, Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, Brazil.|Escola Superior de Ciências da Saúde, Universidade do Estado do Amazonas, Manaus, Brazil.
authors.forename: Tatiana P
authors.initials: TP
authors.lastname: Beltrán
authors.affiliation: Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Kobylinski
authors.affiliation: Escola Superior de Ciências da Saúde, Universidade do Estado do Amazonas, Manaus, Brazil.
authors.forename: Gisely C
authors.initials: GC
authors.lastname: Melo
authors.affiliation: Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brazil.
authors.forename: José B P
authors.initials: JB
authors.lastname: Lima
authors.affiliation: Diretoria de Ensino e Pesquisa, Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, Brazil.
authors.forename: Sara G M
authors.initials: SG
authors.lastname: Silva
authors.affiliation: Diretoria de Ensino e Pesquisa, Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, Brazil.
authors.forename: Íria C
authors.initials: ÍC
authors.lastname: Rodriguez
authors.affiliation: Diretoria de Ensino e Pesquisa, Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, Brazil.|Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Lisbon, Portugal.
authors.forename: Henrique
authors.initials: H
authors.lastname: Silveira
authors.affiliation: Diretoria de Ensino e Pesquisa, Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, Brazil.|Escola Superior de Ciências da Saúde, Universidade do Estado do Amazonas, Manaus, Brazil.
authors.forename: Maria G V B
authors.initials: MG
authors.lastname: Guerra
authors.affiliation: ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain.|Centro de Investigação em Saúde de Manhiça (CISM), Maputo, Mozambique.
authors.forename: Quique
authors.initials: Q
authors.lastname: Bassat
authors.affiliation: Diretoria de Ensino e Pesquisa, Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, Brazil.|Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, Brazil.
authors.forename: Paulo F P
authors.initials: PF
authors.lastname: Pimenta
authors.affiliation: Diretoria de Ensino e Pesquisa, Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, Brazil.|Instituto de Pesquisas Leônidas & Maria Deane, FIOCRUZ, Manaus, Brazil.
authors.forename: Marcus V G
authors.initials: MV
authors.lastname: Lacerda
authors.affiliation: Diretoria de Ensino e Pesquisa, Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, Brazil.|Escola Superior de Ciências da Saúde, Universidade do Estado do Amazonas, Manaus, Brazil.
authors.forename: Wuelton M
authors.initials: WM
authors.lastname: Monteiro
keywords: Amazon; Anopheles aquasalis; Ivermectin; Malaria elimination; Vector control