FibroScan-AST Score vs Liver Stiffness for the Prediction of Liver Events After HCV Cure

Open Forum Infectious Diseases MAJOR ARTICLE FibroScan-AST Score vs Liver Stiffness for the Prediction of Liver Events After HCV Cure Anaïs Corma-Gómez, 1,2,3, Diana Corona-Mata, 3,4,5,6 Jésica Martín-Carmona, 1,2,3,7, María José Galindo, 8 Angela Camacho, 3,4,5,6 Carmen Martín-Sierra, 1,2, Marina Gallo-Marín, 3,4,5,6 Pilar Rincón, 1 Ignacio Perez-Valero, 3,4,5,6 Margarita Pérez-García, 1 Angela Carrasco-Dorado, 4,5,6, Juan A. Pineda, 1,3,7 Antonio Rivero-Juárez, 3,4,5,6, Antonio Rivero, 3,4,5,6 Luis M. Real, 1,2,3,7, and Juan Macías 1,2,3,7 ; on behalf of the GEHEP-011 Study Group 1 Grupo de Virología Clínica e ITS Cinical Virology and STIs Group, Unit of Infectious Diseases and Microbiology, de Hospital Universitario Virgen de Valme, Sevilla, Spain, 2 Instituto de Biomedicina de Sevilla (IBiS)/CSIC, Sevilla, Spain, 3 Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain, 4 Clinical Virology and Zoonoses Research Group, Unit of Infectious Diseases, Hospital Universitario Reina Sofía, Córdoba, Spain, 5 Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain, 6 Universidad de Córdoba (UCO), Córdoba, Spain, 7 Universidad de Sevilla (US), Sevilla, Spain, and 8 Unit of Infectious Diseases, Hospital Clínico Universitario de Valencia, INCLIVA, Valencia, Spain Background. Liver stiffness (LS) predicts liver complication occurrence in patients with hepatitis C virus (HCV) infection after sustained virological response (SVR). The FibroScan-AST (FAST) score, which includes aspartate aminotransferase (AST) and controlled attenuation parameter (CAP; measured by FibroScan), may improve the prediction ability of isolated LS. Our aim was to compare the predictive capacity of LS vs FAST in this setting. Methods. Multicenter cohort study including individuals with HIV/HCV coinfection or HCV monoinfection from Spain if they had (1) LS ≥9.5 kPa pretreatment, (2) SVR with a direct-acting antiviral (DAA)–based regimen, and (3) LS and CAP measurement at SVR. Fatty liver disease (FLD) was defined as CAP ≥248 dB/m. The primary outcome was the occurrence of a liver complication (decompensation or hepatocellular carcinoma [HCC]) after SVR. Results. Three hundred patients were included; 213 (71%) had HIV. At SVR, 131 (44%) had FLD. The FAST score was <0.35 in 182 (61%), 0.35–0.67 in 79 (27%), and >0.67 in 34 (12%) patients. After a median (Q1–Q3) follow-up of 73 (53–83) months, 36 (12%) liver complications (15 [5%] HCC) occurred. LS was independently associated with an increased risk of developing liver complications (sub–hazard ratio [sHR], 1.06; 95% CI, 1.04–1.08; P < .001). In a separate model, FAST ≥0.35 was also independently associated with greater risk of liver complications (sHR, 8.12; 95% CI, 3.11–21.17; P < .001). The area under the receiver operating characteristics curve of the model based on LS was 0.83 (95% CI, 0.76–0.91), and that of the model based on FAST was 0.80 (95% CI, 0.72–0.88; P = .158). Conclusions. The FAST score predicts the development of liver events after SVR but does not improve the predictive capacity of LS alone at this time point. Keywords. FAST score; HCV infection; liver complications; liver stiffness; sustained virological response. Received 15 July 2024; editorial decision 10 October 2024; accepted 12 October 2024; published online 8 April 2025 Correspondence: Anaïs Corma-Gómez, MD, PhD, Unit of Infectious Diseases, Hospital Universitario de Valme, Avenida de Bellavista s/n, 41014 Sevilla, Spain (anais.corgo@gmail. com); or Juan Macías, MD, PhD, Unit of Infectious Diseases, Hospital Universitario de Valme, Avenida de Bellavista s/n, 41014 Sevilla, Spain ([email protected]). Open Forum Infectious Diseases ® © The Author(s) 2025. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons. org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact [email protected] 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 [email protected]. https://doi.org/10.1093/ofid/ofae628 With the availability of direct-acting antiviral (DAA) agents, hepatitis C virus (HCV) chronic infection has become a curable infection in nearly all cases and a potentially eliminable disease. However, liver-related complications may occur in individuals with HCV infection even after achieving sustained virological response (SVR), particularly among those with advanced liver disease [1, 2]. The main challenge remains to find markers that accurately predict clinical outcomes, allowing a more adequate surveillance after SVR. In this setting, liver stiffness (LS), measured by vibration-controlled transient elastography (VCTE), has proven to be a strong predictor of liver events, both during HCV active infection and after HCV cure [3]. Indeed, LS is the reflection of liver fibrosis and inflammation, as well as portal hypertension, so this procedure has a high predictive value for liverrelated outcomes. Namely, a vale ≤14 kPa at the moment of SVR identifies patients with HCV infection, regardless of HIV coinfection, with low risk of developing liver complications, who may be candidates to discontinue surveillance measures [4]. However, the most important concern is that LS by itself is insufficient to detect individuals at high risk for these clinical outcomes, mainly due to a limited positive predictive value. Steatotic liver disease (SLD) is becoming a leading cause of chronic liver disease. SLD is estimated to involve nearly one-third of the global population [5], and it is mainly related to the obesity pandemic [6]. Among patients with HCV infection, the prevalence of concomitant SLD could be higher, up to 50% [7, 8], FibroScan-AST Score vs Liver Stiffness for the Prediction of Liver Events After HCV Cure • OFID • 1 Downloaded from https://academic.oup.com/ofid/article/12/4/ofae628/8103002 by guest on 10 June 2025 due to a direct lipogenic effect of the virus or metabolic dysfunction [9, 10] that may persist after HCV eradication [6, 11]. Concomitant SLD could play a role in the emergence of these liver-related events, enhancing fibrogenesis and hepatocarcinogenesis [12, 13]. The FibroScan-AST (FAST) score, which includes aspartate aminotransferase (AST), controlled attenuation parameter (CAP; measured by VCTE), and LS, is an indicator of steatohepatitis with greater risk of fibrosis progression [14, 15]. The FAST score reliably predicts clinical outcomes in patients with SLD [16, 17]. Consequently, it may also be a better predictor of clinical outcomes than simple LS in patients with HCV infection who achieve SVR. However, information on this is lacking. Therefore, the aim of this study was to compare the predictive value of the FAST score vs LS for liver complications in patients with HCV infection and advanced fibrosis, with or without HIV coinfection, who achieve SVR. METHODS Study Design and Patients This was a multicenter prospective study that included patients with HCV chronic infection, with or without HIV coinfection, from the GEHEP-011 Cohort (clinicaltrials.gov ID: NCT04460157). Individuals were followed at 17 infectious diseases units throughout Spain since October 2011. The inclusion criteria for this study were (1) an LS ≥9.5 kPa before starting treatment, (2) having achieved SVR with regimens containing ≥1 DAA, (3) having an LS available at the time of SVR, and (4) having a CAP measurement at the SVR time point. Patients with positive HBsAg were excluded. Follow-up The date of SVR was considered the baseline time point. Following a common protocol, individuals were clinically and analytically evaluated every 6 months. Participants were followed until the date of death, liver transplant, HCV reinfection, loss follow-up, or censoring date (November 30, 2022). Patients with cirrhosis were managed according to a specific protocol reported elsewhere [18]. In summary, screening of hepatocellular carcinoma (HCC) was performed biannually based on alpha-fetoprotein determination and liver ultrasound examination. In addition, in patients with LS ≥21 kPa, gastroesophageal varices surveillance was performed with serial upper gastrointestinal endoscopy. Diagnosis Criteria Liver events included hepatic decompensations (ascites, gastrointestinal bleeding due to portal hypertension, hepatic encephalopathy, spontaneous bacterial peritonitis, and hepatorenal syndrome) and HCC. Diagnosis of de novo HCC was established according to the American Association for the Study of Liver Diseases criteria [19]. Hepatic decompensations were diagnosed as reported previously [20]. VCTE Examinations LS and CAP were assessed by VCTE (FibroScan, Echosens, Paris, France) according to a standardized procedure. An M probe was used. At each center, examinations were performed by a trained operator. For determinations to be considered reliable, evaluations had to include at least 10 measurements, with a success rate ≥60% and an interquartile range <30% of the median LS. End Point and Other Definitions The primary end point of the study was the emergence of a liverrelated event after SVR. SVR was defined as showing undetectable HCV RNA 12 weeks after the end of DAA-based therapy. In line with previous studies, a diagnosis of cirrhosis was established in individuals with LS ≥14 kPa [4, 21, 22]. SLD was defined as CAP ≥248 dB/m [23]. The FAST score [14], which includes AST, CAP, and LS, was calculated. A FAST score ≥0.67 was interpreted as likely nonalcoholic steatohepatitis (NASH) with fibrosis stage ≥2, and a FAST score ≤0.35 was considered unlikely NASH with fibrosis ≥2. Statistical Analysis The cumulative incidence and incidence rate of liver-related complications were estimated. The time to the emergence of the main outcome was computed as the time elapsed from SVR to liver event occurrence. Life tables were built to calculate the survival estimates, expressed as the cumulative proportion of individuals who remained free from development of the end point. Survival curves were constructed using the Kaplan-Meier method, and the log-rank test was performed to compare the different categories. Variables associated with the main end point in the bivariate analysis with P < .05, along with age and sex at birth, were entered in a multivariable analysis, and Fine-Gray regression models for competing risks were created. Death by any cause was considered the competitive event. The performance of the models was assessed by comparing receiver operating characteristics (ROC) curves using the Hanley-McNeil test. The diagnostic accuracy of the FAST score and LS for the prediction of liver events after SVR was assessed by sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). We calculated the percentage of missed events and the proportion of individuals without hepatic complications identified. All estimates are provided, along with 95% CIs. For the statistical analysis, the statistical package IBM SPSS 26 (SPSS Inc. IBM) and Stata, version 16.1 (StataCorp), were used. Ethics This study was conducted according to the Helsinki Declaration and was approved by the local ethics committee. All patients 2 • OFID • Corma-Gómez et al Downloaded from https://academic.oup.com/ofid/article/12/4/ofae628/8103002 by guest on 10 June 2025 gave written informed consent before being recruited into the cohort. RESULTS Characteristics of the Patients. Three hundred patients were included, 213 (71%) of whom were people with HIV (PWH). One hundred fifty-four (51%) individuals showed compensated cirrhosis before starting DAA therapy. At the SVR time point, 142 (47%) had an LS ≥14.0 kPa. With respect to SLD, at the SVR time point, 131 (44%) had CAP values ≥248 dB/m. The FAST score was <0.35 in 182 (61%), 0.35–0.66 in 79 (27%), and ≥0.67 in 34 (12%) patients. Other relevant characteristics of the study population are listed in Table 1. All PWH were on antiretroviral therapy, and 161 (86%) of them had a plasma HIV-RNA <50 copies/mL. The median (Q1−Q3) CD4+ cell count was 489 (302–679) cells/mm 3 . The median (Q1–Q3) follow-up was 73 (57–83) months. During this time, 44 (15%) patients died, 8 (3%) underwent a liver transplant, and 10 (3%) were lost to follow-up. The main causes of death were liver-related events (16 [36.4%]), non-HCC malignancies (12 [27.3%]), infectious diseases (5 [11%]), and other causes (11 [25.3%]). Liver-Related Events Post-SVR After HCV cure, 36 (12%) patients developed a liver complication. The liver complication rate was 1.9 (1.4–2.6) per 1000 person-years. The probability of remaining free from liverrelated events at 1, 3, and 5 years after the SVR time point was 97% (94%–98%), 92% (88%–94%), and 89% (85%–92%), respectively. Specifically, 22 (7%) individuals had hepatic decompensation, and 15 (5%) patients developed HCC. With respect to liver decompensations, the most frequent one was ascites (12 [4%]), followed by portal hypertensive gastrointestinal bleeding (7 [2%]) and hepatic encephalopathy (3 [1%]). Prediction of Clinical Outcome After SVR The presence of SLD was not associated with the emergence of liver complications after HCV cure (Table 2). The probability of developing the main outcome was greater for patients with LS ≥14.0 kPa and for those with higher FAST scores (Table 2, Figure 1). A first multivariable model was created, adjusted for sex at birth, age, HIV coinfection, emergence of liver events before SVR, and LS at the SVR time point. In this analysis, LS at the SVR time point was independently associated with an increased risk of developing liver complications (Table 2). Other predictors are shown in Table 2. In a second model, adjusted for sex at birth, age, HIV coinfection, emergence of liver events before SVR, FAST score at SVR, and MELD score at the SVR time point, FAST ≥0.35 was independently associated with greater risk of liver complications (Supplementary Table 1). The diagnostic performance of the noninvasive tools studied for the emergence of liver complications after HCV cure is presented in Table 3. LS showed the highest NPV while missing the lowest proportion of clinical events. In addition, LS <14 kPa and FAST score ≤0.35 identified a similar percentage of individuals who did not develop liver complications after SVR. The PPV for the FAST cutoff, 0.67, and the one for LS were all low (Table 3). The AUROC of the model based on LS was 0.83 (95% CI, 0.76–0.91), and that of the model based on FAST 0.80 (95% CI, 0.72–0.88; P = .158) (Figure 2). The sensitivity analysis, including patients with SLD, yielded similar results (Supplementary Data). Sensitivity analyses according to HIV coinfection are shown in the Supplementary Data. DISCUSSION This study suggests that, after SVR, the FAST score is useful to identify individuals with HCV infection and advanced liver disease who are at low risk of developing liver-related outcomes. However, using the FAST score does not improve the predictive ability of simple LS for the emergence of these clinical events. Moreover, LS identifies a similar proportion of patients at low risk of liver complication occurrence while minimizing the number of missed events. Table 1. Baseline Characteristics of the Study Population (n = 300) Parameters Value Before treatment Sex at birth, male, No. (%) 255 (85) Age, y a 52 (48–55) IDUs, No. (%) 229 (76) HCV GT3, No. (%) 58 (19) Cirrhosis (LS ≥14 kPa), No. (%) 191 (64) CPT, class A, No. (%) 283 (94) MELD score a 7 (6–8) Liver complication, No. (%) 37 (12) At SVR time point LS value, a kPa 13.1 (8.8–22.6) Diabetes mellitus, b No. (%) 25 (8.4) Alcohol consumption, ≥50 g/d, c No. (%) 16 (7.2) CPT class A, No. (%) 283 (94) MELD score a 6 (6–8) Platelets count, ×10 9 /µL a 142 (107–187) CAP value, dB/m a 241 (204–273) FAST score a 0.27 (0.12–0.49) Data are No. (%) of patients. Abbreviations: CAP, controlled attenuation parameter; CPT, Child Pugh Turcotte score; FAST, FibroScan-AST; GT3, genotype 3; HCV, hepatitis C virus; IDUs, injection drug users; LS, liver stiffness; MELD, Model for End-Stage Liver Disease score; SVR, sustained virological response. a Median (Q1–Q3). b Available at 297 patients. c Available at 220 patients. FibroScan-AST Score vs Liver Stiffness for the Prediction of Liver Events After HCV Cure • OFID • 3 Downloaded from https://academic.oup.com/ofid/article/12/4/ofae628/8103002 by guest on 10 June 2025 Table 2. Predictors of Liver Complications (n = 300) Parameter Categories No. (%) P bivariate Adjusted SHR (95% CI) P multivariable Sex at birth Male Female 32/255 (12.5) 4/45 (8.9) .461 1.71 (0.53–5.54) .370 Age, y <52 ≥52 15/150 (10.0) 21/150 (14.0) .153 1.04 (0.99–1.08) a .051 IDU No Yes 9/71 (12.7) 27/229 (11.8) .886 — — HCV genotype Others GT3 26/242 (10.7) 10/58 (13.2) .157 — — HIV coinfection Negative Positive 16/87 (12.4) 20/213 (9.4) .014 0.37 (0.17–0.78) .009 Liver complication before DAA No Yes 24/263 (9.0) 12/37 (32.4) <.001 1.20 (0.44–3.28) .719 LS at SVR time point, kPa <14 ≥14 3/158 (1.9) 33/142 (23.2) <.001 1.06 (1.04–1.08) <.001 Alcohol intake, g/d <50 ≥50 28/204 (13.6) 2/16 (12.5) .947 — — Diabetes Mellitus No Yes 34/271 (12.5) 1/25 (4.0) .261 — — MELD at SVR time point <10 ≥10 25/269 (9.3) 11/23 (47.8) <.001 5.11 (2.19–11.92) <.001 CPT class at SVR time point A B or C 31/283 (11.0) 5/10 (50.0) <.001 — — CAP value at SVR time point, dB/m <248 ≥248 20/169 (11.8) 16/131 (12.2) .970 — — Model including LS. The table shows patient characteristics associated with a greater probability of developing liver complications after HCV cure. For the bivariate analysis, continuous variables were categorized according to the median value or using clinically significant cutoff points. Variables associated with the main end point in the bivariate analysis with P < .05, along with age and sex at birth, were entered in a multivariable analysis, and a Fine-Gray regression model for competing was conducted. Death for any cause was considered the competitive event. Age and LS at the SVR time point were entered as a continuous variable, and all other parameters were entered as categorical variables. Abbreviations: CAP, controlled attenuation parameter; CPT, Child Pugh Turcotte score; GT3, genotype 3; HCV, hepatitis C virus; IDU, injection drug user; LS, liver stiffness; MELD, Model for End-Stage Liver Disease score; sHR, sub–hazard ratio; SVR, sustained virological response. a For a 1-unit increase. Figure 1. Probability of remaining free from liver-related outcomes after SVR, according to FAST score. Abbreviations: FAST, FibroScan-AST; SVR, sustained virological response. 4 • OFID • Corma-Gómez et al Downloaded from https://academic.oup.com/ofid/article/12/4/ofae628/8103002 by guest on 10 June 2025 SLD is a growing concern because of its high prevalence, which is increased among individuals with HCV infection [7, 8]. In the present study, the proportion of individuals with SLD was greater than that estimated among the general population [5, 24], which is not surprising. In this setting, the interplay between HCV infection and SLD involves complex interactions that can influence the progression of liver disease. Understanding the contribution of factors such as fibrosis and SLD in this predictive model is crucial for tailoring follow-up care and interventions for individuals with HCV infection who achieve SVR. To date, information on this subject is still scarce. While attaining SVR addresses the direct effects of HCV on the liver, individuals with past HCV infection may still be at risk for metabolic issues, including SLD [6, 11, 25–27]. Indeed, insulin resistance, which is commonly associated with both HCV infection and SLD, might persist after SVR, contributing to metabolic disturbances [28]. In a recent small study, Chuaypen et al. demonstrated that the improvement observed in LS after HCV eradication was not associated with a decrease of hepatic steatosis in a high proportion of the study population [11]. Thus, after SVR, concomitant SLD might put patients with HCV chronic infection at a greater risk of developing liver-related complications, especially among those with advanced liver disease. In that regard, steatohepatitisrelated biomarkers, specifically the FAST score, have proven to be useful for predicting the development of liver-related outcomes in different settings [15]. In the specific context of HCV infection, the presence of steatohepatitis, as indicated by a high FAST score, may contribute to an increased risk of HCC after SVR [17]. The inclusion of AST, CAP, and LS in the FAST score was intended to provide a comprehensive assessment of liver disease, considering both fibrosis and steatohepatitis. This combination aims to capture a broader spectrum of liver conditions that may influence the development of liver complications even after successful HCV treatment. The findings of this study reveal that FAST score was independently associated with a higher risk of developing liverrelated events, aligning with previous studies demonstrating the utility of the FAST score in predicting outcomes in individuals with SLD [17]. However, the comparison of the predictive capacities of LS and the FAST score did not yield a statistically significant difference. Moreover, LS showed a better diagnostic performance than FAST score with a greater NPV, maximizing the proportion of patients without clinical events detected Table 3. Diagnostic Thresholds of FAST Score and LS Assessed at the Time of SVR (n = 300) Se (95% CI) Sp (95% CI) PPV (95% CI) NPV (95% CI) Missed Events, n/N (%) Patients Without Events Identified, n/N (%) FAST ≤0.35 83 (67–93) 67 (61–73) 26 (18–35) 97 (93–99) 6/183 (3.3) 177/300 (59) FAST ≥0.67 33 (18–51) 91 (87–94) 35 (19–53) 91 (87–94) 24/264 (9.1) 240/300 (80) LS ≥14 kPa 92 (77–98) 59 (52–65) 23 (16–31) 98 (94–100) 3/158 (1.9) 155/300 (52) Abbreviations: FAST, FibroScan-AST; LS, liver stiffness; NPV, negative predictive value; PPV, positive predictive value; Se, sensitivity; Sp, specificity; SVR, sustained virological response. Figure 2. ROC curves of FAST score and LS for the prediction of liver-related events. Abbreviations: FAST, FibroScan-AST; LS, liver stiffness; ROC, receiver operating characteristics. FibroScan-AST Score vs Liver Stiffness for the Prediction of Liver Events After HCV Cure • OFID • 5 Downloaded from https://academic.oup.com/ofid/article/12/4/ofae628/8103002 by guest on 10 June 2025 while minimizing the number of missed complications. Finally, the PPV of the FAST score was similar to that of LS for occurrence of liver-related events, suggesting that neither LS nor FAST by itself is useful to accurately identify at-risk individuals. The similar AUROC values between the 2 models indicate that both are similarly effective in identifying individuals at low risk of developing liver complications. This implies that the additional information provided by CAP and AST in the FAST score did not significantly enhance the prognostic accuracy over LS alone. That suggests that fibrosis, whatever the origin is, either residual to prior HCV infection or to coexisting SLD, drives the emergence of complications after HCV cure. This observation raises important clinical implications, suggesting that focusing on fibrosis assessment by means of a simple measurement might be sufficient in this particular post-SVR setting. Consequently, devices measuring SLD in addition to LS are not strictly required to establish the prognosis in this setting. Likewise, simple blood markers of liver fibrosis, such as FIB-4 score, could be useful in settings where LS measurement devices are not available [29]. Definitively, there is a need for markers that, while maintaining the sensitivity and NPV of LS, increase specificity. However, FAST score, even at its upper cutoff value, fails to meet this requirement. Research in this area is imperative. This study may have some limitations. First, the absence of a significant difference in predictive capacity prompts further exploration into the dynamic changes of LS and FAST over longer follow-up periods. It is plausible that the impact of SLD on outcomes may evolve over time, influencing the prognostic value of the FAST score in later stages post-SVR. Second, concomitant comorbidities and factors related to lifestyle have not been analyzed in this study, particularly alcohol intake after SVR. Nonetheless, this is the first study comparing the performance of FAST score and LS for the prediction of liver events after SVR. Moreover, long-term data from a large sample of patients with hepatitis C and advanced liver disease in which individuals are prospectively followed in real-life clinical practice settings are provided. Those are the strengths of this work. In conclusion, the FAST score is independently associated with a higher risk of liver-related events after HCV cure. However, it does not surpass the predictive capacity of LS alone. Focusing on fibrosis assessment through LS or other biomarkers may suffice in this post-SVR setting, rendering additional devices measuring SLD alongside LS not strictly required for prognosis determination. This may be particularly relevant for resource-limited centers that rely on older devices or other types of elastography. Future studies should address SLD dynamic changes after HCV treatment and their impact on outcomes over time, potentially influencing the prognostic value of the FAST score in later stages post-SVR. Supplementary Data Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author. Acknowledgments Author contributions. Conceptualization: A.C.G., J.M., J.A.P., L.M.R.; methodology: A.C.G., J.M., J.A.P.; formal analysis: A.C.G., J.M., J.A.P.; investigation: all authors; resources: all authors; data curation: all authors; writing—original draft: A.C.G., J.M., J.A.P.; writing—review & editing: all authors; visualization: all authors; supervision: L.M.R., J.M., A.C.G., J.A.P.; project administration: A.C.G.; funding acquisition: A.C.G., J.A.P. A.C.G. and J.M. had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Data availability. The data that support the findings of this study are available from the corresponding author (A.C.G.) upon reasonable request. Financial support. This study was partially funded by the Instituto de Salud Carlos III (Project PI19/01443), integrated in the Nacional I + D + i 2013–2016, and cofunded by the European Union (ERDF/ESF, “Investing in your future”), Gilead Biomedical Research Fellowship Program (GLD21_00096), and by GEHEP-SEIMC (GEHEP-011 project). Anaïs Corma-Gómez received a research extension grant, Acción B, Acción para el Refuerzo de la Actividad Investigadora en las Unidades Clínicas del Servicio Andaluz de Salud 2021, Clínicos Investigadores (grant number B-0061-2021). She has also received a Juan Rodès grant from the Instituto de Salud Carlos III (grant number JR23/00066). Juan Macías has received a research extensión grant, Acción A, Acción para el Refuerzo de la Actividad Investigadora en las Unidades Clínicas del Servicio Andaluz de Salud 2021, Intensificación anual (grant number A1-0060-2021). Jésica Martín Carmona is the recipient of a Rio Hortega grant by Instituto de Salud Carlos III-ISCIII (CM23/00255). Diana Corona Mata is the recipient of a Rio Hortega grant by Instituto de Salud Carlos III-ISCIII (CM22/00176). Ángela Carrasco Dorado is the recipient of an “INVESTIGO” research program grant funded by the European Union NextGenerationEU Plan. Antonio River-Juárez is supported by a contract from the Spanish Junta de Andalucía (Nicolas Monardes program: C1-0001-2023). The funders did not play any role in the design, conclusions, or interpretation of the study. Potential conflicts of interest. All authors: no reported conflicts. References 1. Kanwal F, Kramer JR, Asch SM, Cao Y, Li L, El-Serag HB. Long-term risk of hepatocellular carcinoma in HCV patients treated with direct acting antiviral agents. Hepatology 2020; 71:44–55. 2. Corma-Gómez A, Macías J, Téllez F, et al. Kinetics of emergence of liver complications in hepatitis C virus infected patients and advanced fibrosis, with and without HIV-coinfection, after sustained virological response. AIDS 2021; 35: 2119–27. 3. 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