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Context: Chronic hepatitis C virus (HCV) infection outcomes include liver failure, hepatocellular carcinoma (HCC), and liver-related death.Objective: To assess the association between sustained virological response (SVR) and all-cause mortality in patients with chronic HCV infection and advanced hepatic fibrosis.Design, Setting, and Patients: An international, multicenter, long-term follow-up study from 5 large tertiary care hospitals in Europe and Canada of 530 patients with chronic HCV infection who started an interferon-based treatment regimen between 1990 and 2003, following histological proof of advanced hepatic fibrosis or cirrhosis (Ishak score 4-6). Complete follow-up ranged between January 2010 and October 2011.Main Outcome Measures: All-cause mortality. Secondary outcomes were liver failure, HCC, and liver-related mortality or liver transplantation.Results: The 530 study patients were followed up for a median (interquartile range [IQR]) of 8.4 (6.4-11.4) years. The baseline median (IQR) age was 48 (42-56) years and 369 patients (70%) were men. The Ishak fibrosis score was 4 in 143 patients (27%), 5 in 101 patients (19%), and 6 in 286 patients (54%). There were 192 patients (36%) who achieved SVR; 13 patients with SVR and 100 without SVR died (10-year cumulative all-cause mortality rate, 8.9% [95% CI, 3.3%-14.5%] with SVR and 26.0% [95% CI, 20.2%-28.4%] without SVR; P < .001). In time-dependent multivariate Cox regression analysis, SVR was associated with reduced risk of all-cause mortality (hazard ratio [HR], 0.26; 95% CI, 0.14-0.49; P < .001) and reduced risk of liver-related mortality or transplantation (HR, 0.06; 95% CI, 0.02-0.19; P < .001), the latter occurring in 3 patients with SVR and 103 without SVR. The 10-year cumulative incidence rate of liver-related mortality or transplantation was 1.9% (95% CI, 0.0%-4.1%) with SVR and 27.4% (95% CI, 22.0%-32.8%) without SVR (P < .001). There were 7 patients with SVR and 76 without SVR who developed HCC (10-year cumulative incidence rate, 5.1%; 95% CI, 1.3%-8.9%; vs 21.8%; 95% CI, 16.6%-27.0%; P < .001), and 4 patients with SVR and 111 without SVR experienced liver failure (10-year cumulative incidence rate, 2.1%; 95% CI, 0.0%-4.5%; vs 29.9%; 95% CI, 24.3%-35.5%; P < .001).Conclusion: Among patients with chronic HCV infection and advanced hepatic fibrosis, sustained virological response to interferon-based treatment was associated with lower all-cause mortality. [ABSTRACT FROM AUTHOR]

Resistance-associated substitutions (RASs) are mutations within the hepatitis C (HCV) genome that may influence the likelihood of achieving a sustained virological response (SVR) with direct acting antiviral (DAA) treatment. Clinicians conduct RAS testing to adapt treatment regimens with the intent of improving the likelihood of cure. The Canadian Network Undertaking against Hepatitis C (CANUHC) prospective cohort consists of chronic HCV patients enrolled between 2015 and 2023 across 17 Canadian sites. Utilisation of RAS testing was assessed across demographics, clinical characteristics and years. SVR was described for the overall cohort and compared across populations of patients with historically negative predictors of SVR. The detection of key RASs and how this information influenced DAA selection were assessed. 2434 patients were identified with information on RAS testing. 98.3% achieved SVR. Out of the 227 patients tested for RAS, 147 (64.8%) had any detected RAS, and 84 (37.0%) had an NS5A RAS. The proportion of patients with SVR did not differ between RAS-tested (98.3%) and non-tested patients (98.3%; p = 0.99). SVR in those with an NS5a RAS was similar (98.6%) to the overall SVR proportion. Proportions with SVR did not differ between those with and without RAS testing in key subgroups (genotype 1a, genotype 3, prior treatment, cirrhosis). The specific DAA regimen and the addition of ribavirin were not associated with SVR outcome. RAS testing has a minimal influence on antiviral treatment selection. Going forward, there is a reduced role for RAS testing in most clinical scenarios., (© 2025 John Wiley & Sons Ltd.)

Background: Severe flares (ALT ≥ 10×ULN) are a well-recognised adverse outcome after nucleos(t)ide analogue (NA) cessation and may lead to liver failure. Thus, identification of patients at risk for these flares is of major importance., Methods: Data were used from two prospective studies on NA cessation conducted in the Netherlands and Canada. Patients were eligible based on EASL criteria. HBcrAg and anti-HBc levels were measured at end of treatment (EOT) and week 6 (FUW6). Logistic regression was used to study the association with severe flares., Results: Seventy-eight patients were analysed with a mean age of 49 years, 16 (21%) Caucasian and a majority (65%) were treated with Tenofovir. Overall, 22 patients (28%) developed a severe flare, and 29 (37%) patients were retreated. At EOT, higher HBcrAg levels (aOR: 1.97, p = 0.05; ≥ 4log: 47% severe flare vs. < 3log: 19%, p = 0.036), lower anti-HBc (aOR: 0.29, p = 0.036; < 2log: 50% vs. ≥ 3log: 11%, p = 0.029) and higher HBcrAg/anti-HBc-ratio (aOR: 3.17, p = 0.015; ≥ 2: 58% vs. < 1.5: 14%, p < 0.001) were associated with an increased risk of severe flares, adjusted for HBsAg. At FUW6, higher HBcrAg (aOR: 2.91, p = 0.035; ≥ 5log: 83%, < 3log: 4%, p < 0.001), lower anti-HBc (aOR: 0.46, p = 0.29; < 2log: 50% vs. ≥ 3log: 0%, p = 0.003) and higher HBcrAg/anti-HBc-ratio (aOR: 2.19, p = 0.048; ≥ 1.75: 52% vs. < 1.75: 8%, p < 0.001) were associated with an increased risk of severe flares, adjusted for HBV DNA and ALT., Conclusion: Higher HBcrAg, lower anti-HBc and higher HBcrAg/anti-HBc ratio at EOT and during the first weeks of post-treatment follow-up are associated with an increased risk of hepatic flares after NA withdrawal and could therefore potentially be used to select patients eligible for therapy cessation and to identify patients requiring retreatment., Trial Registration: This study was a post hoc and follow-up study of two previously registered clinical trials (NCT01911156 & NTR7001). No new patients were prospectively included., (© 2024 The Author(s). Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background Aims: Pegylated interferon-α (PegIFNα) is of limited utility during immunotolerant or immune active phases of chronic hepatitis B infection but is being explored as part of new cure regimens. Low/absent levels of IFNα found in some patients receiving treatment are associated with limited/no virological responses. The study aimed to determine if sera from participants inhibit IFNα activity and/or contain therapy-induced anti-IFNα antibodies., Approach Results: Pre-treatment, on-treatment, and post-treatment sera from 61 immunotolerant trial participants on PegIFNα/entecavir therapy and 88 immune active trial participants on PegIFNα/tenofovir therapy were screened for anti-IFNα antibodies by indirect ELISA. The neutralization capacity of antibodies was measured by preincubation of sera±recombinant human IFNα added to Huh7 cells with the measurement of interferon-stimulated gene (ISG)-induction by qPCR. Correlations between serum-induced ISG inhibition, presence, and titer of anti-IFNα antibodies and virological responses were evaluated. Preincubation of on-treatment serum from 26 immunotolerant (43%) and 13 immune active (15%) participants with recombinant-human IFNα markedly blunted ISG-induction in Huh7 cells. The degree of ISG inhibition correlated with IFNα antibody titer ( p < 0.0001; r = 0.87). On-treatment development of anti-IFNα neutralizing antibodies (nAbs) was associated with reduced quantitative HBsAg and qHBeAg declines ( p < 0.05) and inhibited IFNα bioactivity to 240 weeks after PegIFNα cessation. Children developed anti-IFNα nAbs more frequently than adults ( p = 0.004) but nAbs in children had less impact on virological responses., Conclusions: The development of anti-IFNα nAbs during PegIFNα treatment diminishes responses to antiviral therapy. Understanding how and why anti-IFNα antibodies develop may allow for the optimization of IFN-based therapy, which is critical given its renewed use in HBV-cure strategies., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Designing and carrying out a controlled human infection (CHI) model for hepatitis C virus (HCV) is critical for vaccine development. However, key considerations for a CHI model protocol include understanding of the earliest viral-host kinetic events during the acute phase and susceptibility of the viral isolate under consideration for use in the CHI model to antiviral treatment before any infections in human volunteers can take place. Humanized mouse models lack adaptive immune responses but provide a unique opportunity to obtain quantitative understanding of early HCV kinetics and develop mathematical models to further understand viral and innate immune response dynamics during acute HCV infection. We show that the models reproduce the measured HCV kinetics in humanized mice, which are consistent with early acute HCV-host dynamics in immunocompetent chimpanzees. Our findings suggest that humanized mice are well-suited to support development of a CHI model. In-silico and in-vivo modeling estimates provide a starting point to characterize candidate viruses for testing in CHI model studies., Competing Interests: Declarations. Competing interests: YI and CTM are PhoenixBio employees. KC has received honoraria from Bristol-Myers Squibb and MSD K.K., AbbVie, Gilead Science, Dainippon Sumitomo Pharma and Mitsubishi Tanabe Pharma and research funding from Gilead Science, Dainippon Sumitomo Pharma, MSD K.K., AbbVie, Eisai, TORAY, Otsuka Pharma, Chugai Pharma, Takeda Pharma and Roche. JJF reports research funding and consulting fees from AbbVie and Gilead. All other authors have nothing to disclose., (© 2024. The Author(s).)

Background: Liver disease assessment is a key aspect of chronic hepatitis C virus (HCV) infection pre-treatment evaluation but guidelines differ on the optimal testing modality given trade-offs in availability and accuracy. We compared clinical outcomes and cost-effectiveness of common fibrosis staging strategies., Methods: We simulated adults with chronic HCV receiving care at US health centers through a lifetime microsimulation across five strategies: (1) no staging or treatment (comparator), (2) indirect serum biomarker testing (Fibrosis-4 index [FIB-4]) only, (3) transient elastography (TE) only, (4) staged approach: FIB-4 for all, TE only for intermediate FIB-4 scores (1.45-3.25), and (5) both tests for all. Outcomes included infections cured, cirrhosis cases, liver-related deaths, costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). We used literature-informed loss to follow-up (LTFU) rates and 2021 Medicaid perspective and costs., Results: FIB-4 alone generated the best clinical outcomes: 87.7% cured, 8.7% developed cirrhosis, and 4.6% had liver-related deaths. TE strategies cured 58.5%-76.6%, 16.8%-29.4% developed cirrhosis, and 11.6%-22.6% had liver-related deaths. All TE strategies yielded worse clinical outcomes at higher costs per QALY than FIB-4 only, which had an ICER of $12 869 per QALY gained compared with no staging or treatment. LTFU drove these findings: TE strategies were only cost-effective with no LTFU. In a point-of-care HCV test-and-treat scenario, treatment without any staging was most clinically and cost-effective., Conclusions: FIB-4 staging alone resulted in optimal clinical outcomes and was cost-effective. Treatment for chronic HCV should not be delayed while awaiting fibrosis staging with TE., Competing Interests: Potential conflicts of interest. Research grants to institution unrelated to this study: R. K. S.—Gilead, AbbVie, Abbott, Roche, and Zydus; J. J. F.—Abbvie, Cepheid and Gilead. Consulting fees unrelated to this study: J. J. F.—Abbvie and Gilead; L. C.—Boston pharmaceutical, Echosens, Gilead, GSK, Madrigal, MSD, Novo Nordisk, Pfizer, Sagimet and Siemens Healthineers. L. C. received speaker fees unrelated to this project from Echosens, Gilead, Inventiva, Madrigal and Novo Nordisk. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: Withdrawal of nucleos(t)ide analog (NA) therapy is associated with hepatitis B surface antigen (HBsAg) loss and sustained, off-therapy partial cure (normal ALT [≤30 U/L males, ≤20 U/L females) with HBV DNA <2000 IU/mL) but should be offered only to those most likely to benefit. HBVRNA may be useful for risk stratification., Methods: The Hepatitis B Research Network Immune-Active Trial prospectively evaluated treatment with tenofovir (TDF) for 192 weeks ± peginterferon-α (PegIFN) for initial 24 weeks followed by protocolized withdrawal of TDF amongst eligible participants (NCT01369212). HBV RNA was evaluated as predictor of ALT flares and sustained partial cure (HBV DNA<2000 IU/mL) 48 weeks after TDF withdrawal., Results: Of 93 participants discontinuing TDF (52 in TDF+PegIFN and 41 in TDF alone), 52 (55.9%) had unquantifiable HBVRNA at end-of-treatment. ALT flares (>5xULN) at 48 weeks off-therapy occurred in 33.3%, with pre-treatment age (≥35 years) and quantifiable HBV RNA at end-of-treatment, the best predictors (AUROC 0.74 and 0.85, training and test set) of ALT flare. A total of 26 (28.3%) had sustained partial cure; 3 (11.5%) with ALT flare. Non-quantifiable HBVRNA and qHBsAg <100 IU/mL at end-of-treatment were the best predictors of sustained partial cure (AUROC 0.84 and 0.93, training and test set). If HBVRNA was quantifiable at end-of-treatment, the likelihood of sustained partial cure was only 3% whereas if HBV RNA was unquantifiable and qHBsAg <100 IU/mL, this likelihood was 73%., Conclusions: HBVRNA is a useful biomarker in predicting likelihood of achieving sustained partial cure and safe withdrawal of NAs., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Stigma is a complex social phenomenon that leads to marginalization and influences the course of illness. In the context of hepatitis C virus (HCV), stigma is a well-documented barrier to accessing care, treatment, and cure. In recent years, HCV rates among women have increased, resulting in an urgent need to address stigma and its harmful effects. The purpose of this concept analysis was to investigate stigma in the context of women living with HCV using Rodgers' evolutionary method., Methods: PubMed, CINAHL, Scopus, Medline, PsycINFO, and Nursing and Allied Health were used to identify articles describing HCV stigma among women. Articles from peer-reviewed journals and geographic locations, published between 2002-2023, were included in the analysis. As specified in Rodgers' evolutionary method, articles were analyzed with a focus on the concept's context, surrogate and related terms, antecedents, attributes, examples, and consequences., Results: Following screening, 33 articles were selected for inclusion in the analysis. Discrimination and marginalization were identified as surrogate and related terms to stigma; and antecedents of stigma were identified as limited knowledge, fear of diagnosis, and disclosure. Prevalent attributes of stigma in the literature were described as feelings of decreased self-worth, negative stereotyping, and fear of transmission. Importantly, HCV stigma among women is unique in comparison to other forms of infectious disease-related stigma, primarily due its impact on women's identity as mothers and caregivers. Stigmatization of women living with HCV resulted in negative consequences to personal relationships and healthcare access due to decreased health-seeking behaviours. Although access to HCV treatment has changed considerably over time, a temporal analysis could not be completed due to the limited number of articles., Conclusions: Stigma in the context of women living with HCV has its own unique antecedents, attributes, and consequences. This enhanced understanding of stigma among women living with HCV has the potential to inform improved and more effective approaches to care, which will be required to reach HCV elimination. Furthermore, this analysis identifies stigma layering and stigma in the direct-acting antiviral  treatment era as areas for more in-depth future inquiry., (© 2024. The Author(s).)

Introduction: Complete viral suppression with nucleos(t)ide analogs (NAs) has led to a profound reduction in hepatocellular carcinoma and mortality among patients with chronic hepatitis B. Finite therapy yields higher rates of functional cure; however, initial hepatitis B virus (HBV) DNA and alanine aminotransferase (ALT) elevations are almost certain after treatment interruption. We aimed to analyze off-treatment outcomes beyond 12 months after NA cessation., Methods: Patients with well-suppressed chronic hepatitis B who were hepatitis B e antigen-negative at NA cessation and remained off treatment without hepatitis B surface antigen (HBsAg) loss at 12 months were included (n = 945). HBV DNA and ALT fluctuations were allowed within the first 12 months. We used Kaplan-Meier methods to analyze outcomes beyond 12 months. Sustained remission was defined as HBV DNA <2,000 IU/mL and ALT <2× upper limit of normal (ULN) and an ALT flare as ALT ≥5× ULN., Results: Cumulative probability of sustained remission was 29.7%, virological relapse was 65.2% with a mean peak HBV DNA of 5.0 ± 1.5 log 10 IU/mL, an ALT flare was 15.6% with a median peak ALT × ULN of 8.3 (5.7-11.3), HBsAg loss was 9.9% and retreatment was 34.9% at 48 months after NA cessation. A single occurrence of virological relapse or an ALT flare within the first 12 months off-treatment were associated with significantly lower rates of sustained remission beyond 12 months., Discussion: Despite allowing for HBV DNA and ALT fluctuations within the first 12 months off-treatment, most patients without HBsAg loss did not maintain a sustained response thereafter. The best candidates for NA withdrawal are patients with low HBsAg levels at NA cessation, and those without profound or recurrent virological and biochemical relapses in the first off-treatment year., (Copyright © 2024 by The American College of Gastroenterology.)

Background & Aims: Flares after nucleos(t)ide analogue (NA) cessation are common and potentially harmful. Predictors of flares are required for risk stratification and to guide off-treatment follow-up., Method: This multicenter cohort study included virally suppressed patients with chronic hepatitis B (CHB) who were hepatitis B e antigen negative at NA cessation. Hepatic flares were defined based on ALT levels of ≥5x, 10x or 20x the upper limit of normal (ULN). Multivariable Cox regression analyses were performed with censoring at retreatment, HBsAg loss or loss to follow-up. A sub-analysis was performed including HBV DNA levels within the first 12 weeks as a time-dependent covariate., Results: Of the 1,552 included patients, 350 developed a flare (ALT ≥5x ULN), of whom 70.6% did within the first year. One-year cumulative incidences for ALT flares ≥5x, ≥10x, ≥20x ULN were 18.6%, 10.2% and 3.4%, respectively. Severity of flares decreased over time, but severe flares still occurred after 1 year. Thirteen patients decompensated after a flare, of whom three died. Flares did not seem to be associated with increased rates of HBsAg loss (adjusted hazard ratio [aHR] 1.42, p = 0.28). Multivariable analyses showed that older age (aHR 1.02, p = 0.001), male sex (aHR 1.57, p = 0.003), HBsAg levels at NA withdrawal (100-1,000 IU/ml; aHR 1.99, p <0.001; >1,000 IU/ml; aHR 2.65, p <0.001) and tenofovir disoproxil fumarate vs. entecavir therapy (aHR 2.99, p <0.001) were predictive of flares (≥5x ULN). Early HBV DNA levels >5log 10 IU/ml were associated with the highest risk of flares (aHR 2.36, p <0.001)., Conclusion: Flares are common after NA withdrawal, especially within the first year and can result in hepatic decompensation and death. Older age, male sex, higher HBsAg levels at end of treatment and tenofovir therapy were associated with a higher risk of flares. Close monitoring and retreatment should be considered if HBV DNA levels exceed 5log 10 IU/ml within the first 12 weeks., Impact and Implications: This is the first large global multi-centered cohort study which provides detailed data about flares after nucleos(t)ide analogue cessation in patients with chronic hepatitis B. Older age, male sex, higher HBsAg levels at end of treatment and tenofovir therapy were associated with a higher risk of flares. These results could guide follow-up after withdrawal, helping clinicians identify high-risk patients and decide when to restart anti-viral therapy, which we recommend if HBV DNA levels exceed 5log 10 IU/ml within the first 12 weeks., Clinical Trial Number: not applicable., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Aims: Despite the availability of highly effective direct-acting antiviral therapy, chronic hepatitis C (CHC) continues to cause a major public health burden. In many high-income countries, treatment rates have been declining, which was exacerbated by the impact of the COVID-19 pandemic, threatening the ability to meet the World Health Organization (WHO)'s targets for eliminating HCV as a public health threat by 2030. We sought to model the impact of CHC in Canada, a resource-rich country with ongoing immigration from HCV-endemic regions; which relies exclusively on risk-based screening for case identification., Approach and Results: We developed an agent-based model to characterize the HCV epidemic in a high-income country with ongoing immigration. Combinations of prevention such as harm reduction, screening, and treatment strategies were considered. Model parameters were estimated from the literature and calibrated against historical HCV data. Sensitivity analyses were performed to assess uncertainty. Under the current status quo of risk-based screening, we predict the incidence of CHC-induced decompensated cirrhosis, HCC, and liver-related deaths would decrease by 79.4%, 76.1%, and 62.1%, respectively, between 2015 and 2030, but CHC incidence would only decrease by 11.1%. The results were sensitive to HCV transmission rate and an annual number of people initiating treatment., Conclusions: Current risk-based screening, and subsequent treatment, will be inadequate to achieve WHO goals. With extensive scale-up in screening, and treatment, the mortality target may be achievable, but the target for preventing new CHC cases is unlikely reachable, highlighting the importance of developing enhanced harm-reduction strategies for HCV elimination., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: The on-going substance use crisis has led to unprecedented rates of hepatitis C virus (HCV) in Canada, with increasing positivity among women who use drugs (WWUD). Despite efforts to reduce barriers to HCV testing and treatment, follow-up remains a major issue., Methods: In this quality improvement project (QIP), we partnered with a short-stay trauma-informed residential drug treatment facility specifically for WWUD, to provide an engaging peer-led HCV education session, followed by low-barrier nurse and peer-led testing and treatment. We sought to evaluate these interventions, as well as determine what factors could improve engagement after women leave., Results: The session was attended by 217 participants, 130 completed the survey and 153 opted into testing. Survey results indicated that participants were highly motivated to access general care as well as HCV testing and treatment. The most frequently reported barriers to testing and treatment were a previous negative test and being asymptomatic, respectively. Follow-up facilitators included a non-judgmental provider (88%), monetary incentives (67%), follow-up phone calls (77%), e-mails (66%) and text messages (58%). Of those who were RNA positive, 5 of 13 initiated treatment on-site. By using the results of the QIP in real-time, 6 of 13 were started after leaving the centre (one pending and one lost to follow-up)., Discussion and Conclusions: The implementation of co-localised peer-led testing and treatment for HCV, along with persistent follow-up efforts, led to increases in linkage to care and treatment. Co-localisation of testing and care with substance-use services, especially if residential, is a viable, low-barrier strategy for increasing linkage to care among WWUD., (© 2023 The Authors. Drug and Alcohol Review published by John Wiley & Sons Australia, Ltd on behalf of Australasian Professional Society on Alcohol and other Drugs.)

Competing Interests: The author has no conflicts to report.

Background: Post-acute sequelae of COVID-19, or long COVID, is a condition characterized by persistent COVID-19 symptoms. As long COVID is defined by clinical criteria after an elapsed period, an opportunity for early intervention may aid in future prophylactic approaches; however, at present, the pathobiological mechanisms are multifactorial. By analyzing early virally infected upper respiratory tract tissue prior to eventual clinical diagnosis, it may be possible to identify biomarkers of altered immune response to facilitate future studies and interventions. Methods: This is a sub-group analysis of samples collected from those with confirmed COVID-19. RNA extraction from nasopharyngeal/mid-turbinate samples, sequencing, and bioinformatic analysis were performed to analyze long COVID and non-long COVID cohorts at day 14 post infection. Differences in mean viral load at various timepoints were analyzed as well as serological data. Results: We identified 26 upregulated genes in patients experiencing long COVID. Dysregulated pathways including complement and fibrinolysis pathways and IL-7 upregulation. Additionally, genes involved in neurotransmission were dysregulated, and the long COVID group had a significantly higher viral load and slower viral clearance. Conclusions: Uncovering early gene pathway abnormalities associated with eventual long COVID diagnosis may aid in early identification. We show that, post acute infection, in situ pathogenic deviations in viral response are associated with patients destined to meet consensus long COVID diagnosis that is entirely dependent on clinical factors. These results identify an important biological temporal window in the natural history of COVID-19 infection and long COVID pathogenesis amenable to testing from standard-of-care upper respiratory tract specimens.