709ed84b257a3cef89bce08b14c49060 pmc_11596025.pdf 9931c6f363f4daaa7efcab38114dd3b3bccf2831 pmc_11596025.pdf 33f5d0c235a2344ee7777118b264523d77946d031fbcff5bf7f31b9001282eb2 pmc_11596025.pdf Title: Association of Liver Damage and Quasispecies Maturity in Chronic HCV Patients: The Fate of a Quasispecies Subject: Viral diversity and disease progression in chronic infections, and particularly how quasispecies structure affects antiviral treatment, remain key unresolved issues. Previous studies show that advanced liver fibrosis in long-term viral infections is linked to higher rates of antiviral treatment failures. Additionally, treatment failure is associated with high quasispecies fitness, which indicates greater viral diversity and adaptability. As a result, resistant variants may emerge, reducing retreatment effectiveness and increasing the chances of viral relapse. Additionally, using a mutagenic agent in monotherapy can accelerate virus evolution towards a flat-like quasispecies structure. This study examines 19 chronic HCV patients who failed direct-acting antiviral (DAA) treatments, using NGS to analyze quasispecies structure in relation to fibrosis as a marker of infection duration. Results show that HCV evolves towards a flat-like quasispecies structure over time, leading also to advanced liver damage (fibrosis F3 and F4/cirrhosis). Based on our findings and previous research, we propose that the flat-like fitness quasispecies structure is the final stage of any quasispecies in chronic infections unless eradicated. The longer the infection persists, the lower the chances of achieving a cure. Interestingly, this finding may also be applicable to other chronic infection and drug resistance in cancer. Keywords: quasispecies diversity; quasispecies maturity; quasispecies fitness; fibrosis; liver damage; antiviral treatment failure Author: Josep Gregori, Marta Ibañez-Lligoña, Sergi Colomer-Castell, Carolina Campos, Damir García-Cehic and Josep Quer Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25 CreationDate: Fri Nov 1 08:05:35 2024 CET ModDate: Fri Nov 1 08:31:37 2024 CET Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 15 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1761115 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- WLENKM+VnURWPalladioL-Bold Type 1 Custom yes yes yes 10 0 UHDFNC+URWPalladioL-Bold Type 1 Custom yes yes yes 16 0 UNDIXL+URWPalladioL-Roma Type 1 Custom yes yes yes 22 0 EMAQUI+URWPalladioL-Ital Type 1 Custom yes yes yes 27 0 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DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Materials and Methods Destination: section.2 Children: Item: Title: Patients Destination: subsection.2.1 Item: Title: Methods Destination: subsection.2.2 Children: Item: Title: RNA Extraction, Amplification, and Deep-Sequencing Destination: subsubsection.2.2.1 Item: Title: NGS Data Treatment Destination: subsubsection.2.2.2 Item: Title: Quasispecies Maturity Destination: subsubsection.2.2.3 Item: Title: Synonymity Destination: subsubsection.2.2.4 Item: Title: Wilcoxon Test and Adjusted p-Values Destination: subsubsection.2.2.5 Item: Title: Effect Size Destination: subsubsection.2.2.6 Item: Title: Results Destination: section.3 Children: Item: Title: Wilcoxon Test and Statistics Destination: subsection.3.1 Item: Title: Effect Size Destination: subsection.3.2 Item: Title: Collected Metrics of All Comparisons Destination: subsection.3.3 Item: Title: Boxplot and ROC Curves for Selected Indicators Destination: subsection.3.4 Item: Title: Synonymity Destination: subsection.3.5 Item: Title: Full Cohort Maturity Characteristics Destination: subsection.3.6 Item: Title: Discussion Destination: section.4 Item: Title: Conclusions Destination: section.5 Item: Title: References Destination: appendix.A. Info: Title: Association of Liver Damage and Quasispecies Maturity in Chronic HCV Patients: The Fate of a Quasispecies Author: Josep Gregori, Marta Ibañez-Lligoña, Sergi Colomer-Castell, Carolina Campos, Damir García-Cehic and Josep Quer Subject: Viral diversity and disease progression in chronic infections, and particularly how quasispecies structure affects antiviral treatment, remain key unresolved issues. Previous studies show that advanced liver fibrosis in long-term viral infections is linked to higher rates of antiviral treatment failures. Additionally, treatment failure is associated with high quasispecies fitness, which indicates greater viral diversity and adaptability. As a result, resistant variants may emerge, reducing retreatment effectiveness and increasing the chances of viral relapse. Additionally, using a mutagenic agent in monotherapy can accelerate virus evolution towards a flat-like quasispecies structure. This study examines 19 chronic HCV patients who failed direct-acting antiviral (DAA) treatments, using NGS to analyze quasispecies structure in relation to fibrosis as a marker of infection duration. Results show that HCV evolves towards a flat-like quasispecies structure over time, leading also to advanced liver damage (fibrosis F3 and F4/cirrhosis). Based on our findings and previous research, we propose that the flat-like fitness quasispecies structure is the final stage of any quasispecies in chronic infections unless eradicated. The longer the infection persists, the lower the chances of achieving a cure. Interestingly, this finding may also be applicable to other chronic infection and drug resistance in cancer. 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