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agents of HEV, suggests that quasispecies structure may play a crucial role beyond single point mutations. Quasispecies structured in a flat-like manner (referred to as flat-like) are considered to possess high average fitness, occupy a significant fraction of the functional genetic space of the virus, and exhibit a high capacity to evade specific or mutagenic treatments. In this paper, we studied HEV and HCV samples using high-depth next-generation sequencing (NGS), with indices scoring the different properties describing flat-like quasispecies. The significance of these indices was demonstrated by comparing the values obtained from these samples with those from acute infections caused by respiratory viruses (betacoronaviruses, enterovirus, respiratory syncytial viruses, and metapneumovirus). Our results revealed that flat-like quasispecies in HEV and HCV chronic infections without RAS are characterized by numerous low-frequency haplotypes with no dominant one. Surprisingly, these low-frequency haplotypes (at the nucleotide level) exhibited a high level of synonymity, resulting in much lower diversity at the phenotypic level. Currently, clinical approaches for managing flat-like quasispecies are lacking. Here, we propose methods to identifying flat-like quasispecies, which represents an essential initial step towards exploring alternative treatment protocols for viruses resistant to conventional therapies.<\/jats:p>","DOI":"10.3390\/microorganisms12051011","type":"journal-article","created":{"date-parts":[[2024,5,17]],"date-time":"2024-05-17T06:53:49Z","timestamp":1715928829000},"page":"1011","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["In-Host Flat-like Quasispecies: Characterization Methods and Clinical Implications"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4253-8015","authenticated-orcid":false,"given":"Josep","family":"Gregori","sequence":"first","affiliation":[{"name":"Liver Diseases-Viral Hepatitis, Liver Unit, Vall d\u2019Hebron Institut of Research (VHIR), Vall d\u2019Hebron Barcelona Hospital Campus, Passeig Vall d\u2019Hebron 119-129, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergi","family":"Colomer-Castell","sequence":"additional","affiliation":[{"name":"Liver Diseases-Viral Hepatitis, Liver Unit, Vall d\u2019Hebron Institut of Research (VHIR), Vall d\u2019Hebron Barcelona Hospital Campus, Passeig Vall d\u2019Hebron 119-129, 08035 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Av. 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