Prediction model of hepatocellular carcinoma development in chronic hepatitis B virus infection in Spanish cohort

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=> "Prediction model of hepatocellular carcinoma development in chronic hepatitis B virus infection in Spanish cohort" "tieneTextoCompleto" => true "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Paula Gavilán, Juan-Carlos Gavilán, Rocío Arnedo, Encarnación Clavijo, Isabel Viciana, José-Antonio González-Correa" "autores" => array:6 [ 0 => array:3 [ "nombre" => "Paula" "apellidos" => "Gavilán" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 1 => array:4 [ "nombre" => "Juan-Carlos" "apellidos" => "Gavilán" "email" => array:1 [ 0 => "jc_gavilan@hotmail.com" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] 2 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 2 => array:3 [ "nombre" => "Rocío" "apellidos" => "Arnedo" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "Encarnación" "apellidos" => "Clavijo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "d" "identificador" => "aff0020" ] ] ] 4 => array:3 [ "nombre" => "Isabel" "apellidos" => "Viciana" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "e" "identificador" => "aff0025" ] ] ] 5 => array:3 [ "nombre" => "José-Antonio" "apellidos" => "González-Correa" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:5 [ 0 => array:3 [ "entidad" => "Universidad de Málaga, IBIMA-Plataforma BIONAND, Departamento de Farmacología y Pediatría, Facultad de Medicina, Campus de Teatinos s/n, 29071 Málaga, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Departamento de Medicina Interna, Hospital Universitario Virgen de la Victoria, Málaga, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Hospital Internacional Vithas Xanit, Benalmádena, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Universidad de Málaga, IBIMA-Plataforma BIONAND, Departamento de Microbiología, Facultad de Medicina, Campus de Teatinos s/n, 29071 Málaga, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Departamento de Microbiología, Hospital Universitario Virgen de la Victoria, Málaga, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Modelo de predicción del desarrollo de carcinoma hepatocelular en infección crónica por el virus de la hepatitis B en una cohorte española" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1671 "Ancho" => 2150 "Tamanyo" => 302022 ] ] "descripcion" => array:1 [ "en" => "The cumulated incidence of HCC throughout the follow-up in each of the risk groups established from the optimal cut-off point indicated for each score (A: HCCB; B: aMAP; C: PAGE-B; D: REACH-B)." ] ] ] "textoCompleto" => "IntroductionLiver cancer is the seventh most prevalent cancer in 2020 worldwide and the third leading cause of cancer-related mortality.<a class="elsevierStyleCrossRef" href="#bib0155">1</a> Hepatocellular carcinoma (HCC) is the most common primary liver cancer, with a higher incidence in patients with liver cirrhosis.<a class="elsevierStyleCrossRef" href="#bib0160">2</a> Its distribution worldwide is heterogeneous and is related to the broad variability in the prevalence of the different risk factors associated with the development of the disease. Chronic hepatitis B virus (CHB) infection remains the leading cause of HCC globally, with areas of high incidence, such as East Asia, Micronesia, Sub-Saharan Africa and Southeast Asia, where age-specific rates range from 13.3 to 17.7×100,000 inhabitants.This fact is closely related to the high prevalence of chronic B virus infection in the aforementioned areas (prevalence rates ranged from 3.5 to 7.5%). In contrast to the incidence of HCC in Western Europe, Mediterranean countries and North America with HCC age-specific incidence rates ranging from 5.3 to 6.8×100,000 inhabitants in which the prevalence of chronic hepatitis B (CHB) ranged from 0.5 to 1.5%.<a class="elsevierStyleCrossRef" href="#bib0165">3</a> In addition to the development of established cirrhosis, many other factors have been related to an increased risk of hepatocellular carcinoma in patients with chronic hepatitis B virus infection; some of them are host-dependent as genetic factors, male gender,<a class="elsevierStyleCrossRef" href="#bib0170">4</a> age,<a class="elsevierStyleCrossRef" href="#bib0175">5</a> liver steatosis,<a class="elsevierStyleCrossRef" href="#bib0180">6</a> diabetes<a class="elsevierStyleCrossRef" href="#bib0185">7</a> and alcohol intake,<a class="elsevierStyleCrossRef" href="#bib0190">8</a> and others depend on viral factors such as infection with positive HBeAg variants,<a class="elsevierStyleCrossRef" href="#bib0195">9</a> genotype and viral mutations,<a class="elsevierStyleCrossRef" href="#bib0200">10</a> coinfection with hepatitis C virus,<a class="elsevierStyleCrossRef" href="#bib0205">11</a> and degree of viral hepatitis B replication.<a class="elsevierStyleCrossRef" href="#bib0210">12</a>Antiviral treatment has enabled the inhibition of viral replication and has significantly attenuated necro-inflammation and resultant fibrosis in patients with chronic hepatitis B. Nevertheless, the risk of HCC is reduced but not eliminated in patients undergoing effective antiviral therapy.<a class="elsevierStyleCrossRef" href="#bib0215">13</a>The annual incidence of HCC ranges from 0.01% to 5.4% in patients with chronic hepatitis B treated with antiviral.<a class="elsevierStyleCrossRef" href="#bib0220">14</a> The success of treatment for HCC largely depends on the stage at which it is diagnosed, with 5-year survival rates of 70–75% if HCC is diagnosed at an early stage<a class="elsevierStyleCrossRef" href="#bib0225">15</a> and a survival time of 1 year or less if the diagnosis is made at an advanced stage.<a class="elsevierStyleCrossRef" href="#bib0230">16</a> Therefore, an effective and successful HCC surveillance program would offer early diagnosis and improve prognosis.Nonetheless, applying a standardized policy for antiviral therapy and HCC surveillance to all patients with chronic hepatitis B could be burdensome and not cost-effective. Previous studies have shown that surveillance programs are considered cost-effective when the annual incidence of HCC exceeds 1–2%.<a class="elsevierStyleCrossRef" href="#bib0235">17</a> Thus, stratification of the risk of HCC in chronic hepatitis B is helpful for proper management, and it allows identification of high-risk groups.Long-term screening in cohorts of patients with chronic HBV infection for the early diagnosis of liver cancer consumes time and healthcare resources. Therefore, it is important to identify those high-risk carriers in whom screening will be cost-effective.The aim of the study is to identify clinical and viral factors linked to the development of hepatocarcinoma in an unselected cohort of European patients with chronic hepatitis B virus infection in southern Spain treated under the recommendations of the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD).This study aimed to develop a clinical score useful for the identification of high-risk patients, which provides the opportunity to efficiently use clinical resources for early cancer detection in a cost-effective manner. We checked the diagnostic accuracy of the developed score (HCCB) along with three of the main scores from different models that have proven to be useful for this purpose.Material and methodsA longitudinal cohort study with retrospective data review of 453 patients with chronic hepatitis B virus infection was conducted between January 1991 and December 2022 in the liver units of two Hospitals in Málaga (Spain). Seven patients diagnosed with HCC during the first evaluation were excluded. This study was approved by the ethics boards of both of the hospitals.Demographic, main biochemical and viral variables used in the statistical analysis were obtained in the initial evaluation of patients and collected retrospectively. We reported viral loads in IU/mL; however, for statistical analysis, they were converted into log10 IU/mL. In patients whose viral load was below the detection limit (15IU/mL), this value was used for log10 transformation.Successive clinical assessments were performed at 6-month intervals, including alpha-fetoprotein and ultrasound checks. Contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) was performed when a nodule suspected to be an HCC was detected on ultrasonography. Nodules without typical imaging findings were analyzed using tumor biopsy. HCC was diagnosed according to the criteria defined by the American Association for the Study of Liver Disease.<a class="elsevierStyleCrossRef" href="#bib0240">18</a>Authors declared that the research was conducted according to the principles of the World Medical Association Declaration of Helsinki “Ethical Principles for Medical Research Involving Human Subjects”.Statistical analyses were performed using the Statistical Program for Social Sciences (SPSS 20.0 for Windows; SPSS Inc., Chicago, IL, USA).A Kaplan–Meier analysis was performed to obtain curves with a time-to-events method to determine the HCC incidence. A Cox proportional hazard model was used to estimate the multivariable-adjusted hazard ratios.We performed a multivariate regression analysis in a non-automated manner until we reached a model with maximum predictability based on the Cox proportional risk model. A previous assessment was performed to exclude multicollinearity between the predictor variables using an analysis of the variance inflation factor (VIF) and the maximum value of the condition index.The adjusted hazard ratio (HR) values were weighted to create a score to determine the risk of liver cancer (HCCB) and identify low and high-risk groups.The utilization of ROC curves and computation of the area under the curve (AUROC) enabled us to compare the predictive power of our score with three of the main models utilized in clinical practice to identify subgroups at high risk for HCC development, named aMAP,<a class="elsevierStyleCrossRef" href="#bib0245">19</a> PAGE-B<a class="elsevierStyleCrossRef" href="#bib0250">20</a> and REACH-B.<a class="elsevierStyleCrossRef" href="#bib0255">21</a>Finally, we analyzed the characteristics of the tests considered positive in the identification of the high-risk group for liver cancer and obtained them from the identification of the optimal cut-off point in the ROC curves of the four scores applied.ResultsThe initial evaluation of the original cohort revealed the presence of liver cancer in 7 of the 453 patients; all of them were excluded from the study. The remaining 446 patients (280 males and 166 females) were included in the study, with a follow-up time ranging from 0.5 to 31.5 years (mean: 13.8±9.5 years; median: 11.4 years).The median age of the males was 44.7 years (SD: 14.5) vs. 42.5 years (SD: 13.9) for females; p: 0.015. Infection with HBeAg negative hepatitis B virus occurred in 385 out of 446 patients (86.3%). HBeAg positive infection was more frequent in males (OR: 3.97; 95% CI 1.9–8.3; p<0.001) and in patients with a risk of sexual exposition (OR: 3.68; 95% CI 1.98–6.84); they had a higher viral replication (7.17 log10 (SD: 1.51) vs. 3.37 log10 (SD: 1.90); p<0.001) and a higher prevalence of infection by genotypes other than D (OR: 3.39; 95% CI 1.75–6.58; p<0.001) than those with the HBeAg negative variety.There was a concurrent infection with the hepatitis C virus in 29 patients (6.5%) and in 8 patients (1.8%) with Delta virus. Coinfection with two or more hepatitis viruses was more frequent in men (OR: 2.06; 95% CI 0.95–4.48; p: 0.061) and in patients with risk factors for parenteral exposure (OR: 12.2; 95% CI 5.9–25.2; p<0.001). Patients with coinfection with other viruses had lower HBV viral replication compared with those with infection by HBV alone (2.70 log10 [SD: 2.28] vs. 3.99 log10 [SD: 2.25]; p<0.002).The ethnicity of the patients in our cohort was mostly Western European (81%), followed by African (7.3%), Eastern European (6.2%), Asian (4.6%) and South American patients (0.9%). European patients were older than non-Europeans (46.8 years [SD: 14.7] vs. 36.8 years [SD: 10.7]; p<0.001).One hundred sixty patients (36.6%) received antiviral treatment: 29 (18.1%) were treated with a temporary schedule of interferon, and 150 (81.9%) were treated with nucleos(t)ide analogs with or without previous interferon treatment.The viral genotype could be identified in 245 patients (54.0%). The prevalence of the different genotypes and their peak viral loads according to the ethnic origin of the patients is described in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Hepatocellular carcinoma (HCC) was detected in 21 of 446 patients (4.7%) along the follow-up with a global incidence density rate of 0.33 tumors per 100 patients-year.The factors linked to the risk of liver cancer throughout the follow-up period were identified using bivariate Cox regression analysis and included classifying and continuous predictor variables. Some of the latter, such as age, DNA-HBV levels, or Child-P score, were transformed into classifying variables with cut-off points chosen in relation to values of clinical and statistical significance published in previous studies. The findings are outlined in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Variables such as the IL28 B genotype (TT vs. CT and CC) were statistically associated with an increased risk of HCC in the univariate analysis (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).This finding has already been described by some authors in the scientific literature.<a class="elsevierStyleCrossRef" href="#bib0260">22</a> However, it was not included in the multivariate analysis because it could only be tested in just over 58% of the cohort.Similarly, we found a direct relationship between transient elastography values and HCC risk (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). However, this parameter could only be tested in just over 50% of the patients, and in many of them, it was performed during follow-up and not during the baseline assessment. Therefore, it was not included in the multivariate analysis. For the same reason, we did not test our cohort with models that included transient elastography in their scores.<a class="elsevierStyleCrossRef" href="#bib0265">23</a>The variables included in the multivariate Cox regression analysis that behaved as independent factors associated with the development of HCC are shown in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>.<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Factor's weights were taken as the corresponding estimated coefficients in Cox regression analysis after being divided by the smallest coefficient and rounded to the nearest integer. The weighted adjustment of the hazard ratio values obtained in the multivariate analysis allowed the elaboration of a predictive score to assess the risk of HCC (HCCB), as follows:Child score (1.15 points if the value is 6 or higher; 0 points if it is 5)+gender (2.19 points for males; 0 points for females)+coinfection HBV-HCV (1.07 points for coinfection; 0 points without coinfection)+glucose values (1.09 points if it is above 126mg/dL)+alkaline phosphatase (1.51 if the value is greater than 147UI/mL)+Age (3.22 points for patients older than 45 years)+DNA-VHB (1 point if values are higher than 20,000IU/mL).The application of this score in our cohort obtained the following values:Minimum value: 0 point; maximum: 10.16. Mean 3.82. 33rd percentile: 3.19. 66th percentile: 5.41.The use of ROC curves and the determination of the area under the curve (AUROC) showed that the diagnostic accuracy to classify correctly patients for the HCCB score was 0.878 (95% CI 0.797–0.959), a value slightly higher than obtained for aMAP score: 0.753 (95% CI 0.652–0.853), PAGE-B score: 0.773 (95% CI 0.693–0.854), and REACH-B score: 0.730 (95% CI 0.635–0.826) when they were applied to our cohort (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>The optimal cut-off point was estimated in the ROC curves for each of the models. For the HCCB score, the optimal cut-off value was chosen from the coordinates of the curve for a sensitivity value of 0.905 and a 1−specificity value of 0.406. In the remaining scores, the optimal cut-off point applied was the one described by the authors, from which it was possible to differentiate the two risk groups for the development of HCC in the HBV cohort.Using Kaplan–Meier analysis and applying the Log-Rank test, we determined the cumulative incidence of HCC throughout the follow-up in each of the risk groups established from the optimal cut-off point indicated for each score. These are represented in <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>A–D.<elsevierMultimedia ident="fig0010"></elsevierMultimedia>A value greater than 5.39 points was estimated as the cut-off limit for considering the diagnostic test as positive in the discrimination of patients with high and low risk for HCCB. This high-risk group included 193 of the total of 446 patients (43.3%) and 19 of the 21 patients who developed HCC during the follow-up, with an incidence density rate for this group of 1.13 HCC per 100 patients per year.The low-risk group accounted for 253 of the total 446 patients (56.7%). Only two of the 21 patients who developed HCC (9.5%) belonged to this group, with an incidence density rate of 0.05 tumors per 100 patient per year, significantly lower than the high-risk group (Log-Rank p<0.001).<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>A shows the cumulative incidence of HCC among the high and low-risk groups estimated from the optimal cut-off point for the HCCB score, as well as the number and percentage of patients in the cohort included in each of the risk groups, which allows the estimation of the degree of efficiency of the model.<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>B–D represents the cumulative incidence of HCC estimated from the optimal cut-off point for the high and low-risk groups for the aMAP score (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>B), PAGE-B score (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>C), and REACH-B score (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>D), respectively. These figures show the number of patients included in each risk group.In <a class="elsevierStyleCrossRef" href="#sec0060">supplementary material</a>, we can observe the characteristic of the tests considered diagnostic for classifying high- and low-risk groups of HCC in our cohort based on the values of HCCB, aMAP, PAGE-B, and REACH-B scores, defined from the optimal cut-off point of the different ROC curves, including the Youden index, sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio.Finally, we evaluated whether patients with a score greater than 5.39 points on the HCCB were not only at a higher risk of developing HCC, but also whether this fact has prognostic translation into complications or liver-related mortality. To this end, we analyzed a combined variable that included the development of complications due to portal hypertension, need for liver transplantation, or death from a hepatic cause. The results are shown in <a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>.<elsevierMultimedia ident="fig0015"></elsevierMultimedia>DiscussionNatural history studies in untreated patients have reported annual HCC incidences of 0.3–0.6% in non-cirrhotic patients with CHB and 2.2–3.7% in compensated cirrhotic patients, with the highest rates observed in Asia.<a class="elsevierStyleCrossRef" href="#bib0270">24</a>In non-cirrhotic patients treated with entecavir or tenofovir, annual HCC incidence ranges from 0.0% to 1.4% in Asian patients and from 0.1% to 1.0% in predominantly Caucasian populations. In cirrhotic patients treated with entecavir or tenofovir, HCC rates were approximately 4–5 times higher than in those without cirrhosis, ranging from 0.9% to 5.4% in Asians and from 1.5% to 5.2% in Caucasians.<a class="elsevierStyleCrossRef" href="#bib0220">14</a>Based on this principle, all patients with cirrhosis should be screened. For patients without cirrhosis, age, sex, race, viral replication, and family history can determine when and who should be screened.<a class="elsevierStyleCrossRef" href="#bib0275">25</a>Cohorts of patients with hepatitis B in western countries include patients with cirrhosis and chronic hepatitis with viral activity and variable degrees of fibrosis on antiviral treatment, along with patients in stages in which current clinical guidelines do not contemplate antiviral treatment but in which other factors that do not depend on viral activity at the time of evaluation may have an impact on the risk of HCC.The inclusion of cirrhotic patients in the screening surveillance program for the early diagnosis of HCC was not questioned. However, the histological diagnostic reliability of cirrhosis is not always available, and the diagnostic accuracy of elastography, ultrasonography, and panels are far from excellent and can be underestimated, especially in the early stages. Thus, cirrhosis may be misclassified and further affect the performance of models containing cirrhosis as a predictor. Therefore, the clinical utility of these models in cirrhotic patients and the reason for not including them in the model are doubtful. Some authors believe that future risk model studies should focus on non-cirrhotic patients.<a class="elsevierStyleCrossRef" href="#bib0280">26</a>Multivariate Cox regression includes variables commonly used in clinical practice that were significant in the univariate analyses, which can be grouped as host-dependent factors (sex and age), virus-dependent factors (pre-treatment peak viral load levels), stages of liver function (Child or ALBI), and comorbidity (coinfection with hepatitis C, abusive alcohol intake or nonalcoholic steatosis).Although not included in our model, we consider that the baseline value of transient elastography could improve its predictive ability by facilitating the detection of cases with significant fibrosis in patients in the precirrhotic or early stages. At the same time, it could behave as a surrogate marker of factors possibly linked to the risk of HCC, such as significant hepatic steatosis.<a class="elsevierStyleCrossRef" href="#bib0285">27</a>The results obtained from the four models tested in our cohort showed good discriminative accuracy in classifying patients into groups at high and low risk of developing HCC, with AUROC ranging between 0.87 for HCCB and 0.73 for REACH-B. The Youden index for the optimal cut-off point calculated in each of the models is shown as <a class="elsevierStyleCrossRef" href="#sec0060">supplementary material</a> and showed a higher value for HCCB.The sensibility for positive tests obtained from the determination of the optimal cut-off point in the ROC curves is higher for HCCB and lower for REACH-B, with a positive likelihood ratio ranging from 2.83 for HCCB and 1.70 for REACH-B, which allows us to identify one HCC for every eight positive tests in our score compared to one in nine and a half, ten and thirteen positive tests in aMAP, PAGE-B and REACH-B, respectively (<a class="elsevierStyleCrossRef" href="#sec0060">supplementary material</a>). The proportion of patients in the high-risk group ranged from 36.3% in the cohort for aMAP score to 49.2% for REACH-B (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>A–D).However, the most important value when comparing different predictive models is a negative predictive value (NPV) for low-risk groups greater than 99%, as shown in the HCCB (<a class="elsevierStyleCrossRef" href="#sec0060">supplementary material</a>). It identifies a low-risk population with an incidence density of 0.05 HCC/100 person-years, below the value of 0.2% considered cost-effective for non-cirrhotic patients, corresponding to a percentage of 56.7% of the cohort, in which the standard screening established in the guidelines could be questioned, especially among patients without antiviral treatment, circumstance previously pointed out by other authors.<a class="elsevierStyleCrossRef" href="#bib0290">28</a>Finally, it should be noted that the proportion of patients receiving antiviral treatment was significantly higher in the high-risk group compared to the low-risk group (51.6% vs. 29.6%; p: 0.001). However, 48.9% of the patients did not receive it because they did not meet the current clinical criteria for it.The main weakness of our study is the absence of a cohort of validation to confirm the proper functioning of the score developed. In the initial design, we assessed the possibility of carrying out the study on a random sample of 75% of our cohort and applying it to the rest. But the number of patients made us give up on it.Therefore, the results obtained in our model must be validated in external cohorts of unselected Western patients undergoing treatment under conditions accepted in clinical guidelines, in which the incidence of HCC is lower than that obtained in Asian or selected cohorts treated with antiviral agents. In Western unselected cohorts, additional factors associated with to HBV infection, such as coinfection with other viruses, alcohol consumption or prevalence of non-alcoholic steatosis linked to diabetes and obesity, may play a pathogenic role in the risk of HCC development, as well as in the older age of the patients due to different transmission mechanisms compared to the Asian population.In any case, we consider that the staging of HCC risk established by the model we describe, or any other model, should always be complementary to the consideration of the high risk of HCC after the diagnosis of liver cirrhosis.<a class="elsevierStyleCrossRef" href="#bib0295">29</a>Nonetheless, the fact that HBV-associated HCC may also occur in non-cirrhotic livers, suggests that in addition to stimulating host immune response and driving chronic necrotizing inflammation in the liver, HBV also plays a direct role in liver transformation by triggering common and cause-specific oncogenic pathways,<a class="elsevierStyleCrossRef" href="#bib0300">30</a> and justifies the search for predictive risk models beyond the diagnosis of cirrhosis itself.Finally, given the evolving nature of the disease, the risk assessment established by predictive models should be reassessed periodically, possibly every ten years.Ethical approvalThis study was approved by the Institutional Ethics Committee of both the hospitals in Malaga.FundingNone declared.Authors’ contributionsPaula Gavilán Franco: investigation, writing of the original draft, data analysis, and visualization. Juan Carlos Gavilán Carrasco: conceptualization, methodology, software, formal analysis, project administration. Rocío Arnedo: writing review, edition, investigation. Encarnación Clavijo and Isabel Viciana: writing the review, edition, and investigation. Jose Antonio Gonzalez Correa: conceptualization, writing review and supervision.Informed consentPatient consent was waived due to the exemption authorized by both Ethics Committees because it was a retrospective study with a high number of patients and the data collected was anonymized.Authors declared that the research was conducted according to the principles of the World Medical Association Declaration of Helsinki “Ethical Principles for Medical Research Involving Human Subjects”.Conflict of interestThe authors declare no conflict of interest.Data availabilityNo new data were created or analyzed in this study. Data sharing was not applicable in this study." "textoCompletoSecciones" => array:1 [ "secciones" => array:15 [ 0 => array:3 [ "identificador" => "xres2273842" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction and objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1895065" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres2273841" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Antecedentes y objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Materiales y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1895064" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Material and methods" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Ethical approval" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Funding" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Authors’ contributions" ] 11 => array:2 [ "identificador" => "sec0040" "titulo" => "Informed consent" ] 12 => array:2 [ "identificador" => "sec0045" "titulo" => "Conflict of interest" ] 13 => array:2 [ "identificador" => "sec0050" "titulo" => "Data availability" ] 14 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2024-03-11" "fechaAceptado" => "2024-07-27" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1895065" "palabras" => array:3 [ 0 => "Hepatitis B virus" 1 => "Hepatocarcinoma risk factors" 2 => "Prediction model of hepatocarcinoma development" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1895064" "palabras" => array:3 [ 0 => "Virus de la hepatitis B" 1 => "Factores de riesgo de hepatocarcinoma" 2 => "Modelo de predicción del desarrollo de hepatocarcinoma" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "Introduction and objectivesTo identify risk factors associated with the development of hepatocellular carcinoma (HCC) in an unselected cohort of patients with chronic B virus infection (CHB) in Spain. A predictive model was developed to assess the risk of HCC. Material and methodsA prospective open-cohort study recruited 446 unselected patients with chronic hepatitis B infection from two hospitals in Málaga (Spain). The follow-up time ranged from 0.5 to 31.5 years (mean: 13.8; SD: 9.5; median: 11.4 years). We used a Cox proportional hazard model to estimate the multivariable-adjusted hazard ratios of risk factors associated with the development of liver cancer and developed a clinical score, (HCCB score) to determine the risk of liver cancer, that categories patients into two risk levels for the development of HCC. We compared the diagnostic accuracy of our model with other previously published. ResultsDuring the follow-up period, 4.80% of the patients developed liver cancer (21 out of 437), 0.33 cases per 100 patient-years. Multivariate Cox regression analysis revealed that age >45 years, male gender, hepatitis C coinfection, alkaline phosphatase >147IU/L, Child score >5 points, glucose >126mg/dL, and a viral load >4.3 log10 IU/mL were independent risk factors. A risk score has been developed with a high predictive capacity for identifying patients at high risk of developing hepatocellular carcinoma. AUROC 0.87 (95% CI: 0.79–0.95). ConclusionsAn HCCB score greater than 5.42 points identifies a subgroup of chronic hepatitis B patients at high risk of developing liver cancer, who could benefit from screening measures for the early diagnosis of HCC." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction and objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "Antecedentes y objetivoIdentificar loa factores de riesgo asociados al desarrollo de carcinoma hepatocelular (CHC) en una cohorte no seleccionada de pacientes con infección crónica por virus de la hepatitis B en España. Desarrollo de un modelo predictivo para evaluar el riesgo de desarrollo de hepatocarcinoma. Materiales y métodosSe trata de un estudio prospectivo de cohortes abiertas donde se reclutó a 446 pacientes no seleccionados con infección crónica por hepatitis B en 2 hospitales de Málaga (España). El tiempo de seguimiento osciló entre 0,5 y 31,5 años (media: 13,8; DE: 9,5; mediana: 11,4 años). Utilizamos un modelo de riesgos proporcionales de Cox para estimar los cocientes de riesgos ajustados para múltiples variables de los factores de riesgo asociados con el desarrollo de cáncer hepático y desarrollamos un score clínico (HCCB) para determinar el riesgo de desarrollo de hepatocarcinoma, que clasifica a los pacientes en 2 niveles de riesgo para su desarrollo. Comparamos la precisión diagnóstica de nuestro modelo con otros publicados previamente. ResultadosDurante el seguimiento, el 4,80% de los pacientes desarrollaron hepatocarcinoma (21 de 437); 0,33 casos por 100 pacientes/año. El análisis multivariante de regresión de Cox reveló que la edad >45 años, el sexo masculino, la coinfección por hepatitis C, la fosfatasa alcalina >147UI/l, la puntuación Child >5 puntos, la glucosa >126mg/dl y una carga viral >4,3Log10UI/ml eran factores de riesgo independientes. Desarrollamos un score con una alta capacidad predictiva para identificar a los pacientes con alto riesgo de desarrollar CHC. AUROC: 0,87; IC 95%: 0,79-0,95. ConclusionesUna puntuación HCCB superior a 5,42 puntos identifica a un subgrupo de pacientes con hepatitis B crónica con alto riesgo de desarrollar CHC, que podrían beneficiarse de medidas de cribado para el diagnóstico precoz del mismo." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Antecedentes y objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Materiales y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:4 [ "apendice" => "The following are the supplementary data to this article:<elsevierMultimedia ident="upi0005"></elsevierMultimedia>" "etiqueta" => "Appendix B" "titulo" => "Supplementary data" "identificador" => "sec0060" ] ] ] ] "multimedia" => array:7 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1458 "Ancho" => 1708 "Tamanyo" => 122335 ] ] "descripcion" => array:1 [ "en" => "COR curve graphic setting the accuracy diagnosis of HCCB score to correctly classify patients at risk of HCC obtained from our cohort, as well as the curves obtained by applying three of the most used hepatocarcinoma predictive scores of HCC risk (aMAP, PAGE-B and REACH-B). It represents the area under curve (AUROC) for the four indicators with their confidence's intervals." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1671 "Ancho" => 2150 "Tamanyo" => 302022 ] ] "descripcion" => array:1 [ "en" => "The cumulated incidence of HCC throughout the follow-up in each of the risk groups established from the optimal cut-off point indicated for each score (A: HCCB; B: aMAP; C: PAGE-B; D: REACH-B)." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1644 "Ancho" => 2175 "Tamanyo" => 127175 ] ] "descripcion" => array:1 [ "en" => "This figure shows the differences in the survival curves for HCCB risk groups in the hepatitis B cohort, with a statistically worse prognosis for the combined prognostic variable in the high-risk group (HCCB score >5.39) vs. low-intermediate risk group (HCCB score <5.39)." ] ] 3 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Asians and South Americans had higher viral loads compared to the others (ANOVA; p=0.003).Viral load log10 genotypes B+C (Asian patients) were significantly higher than others: 6.0 log10 (SD: 1.8) vs. 4.9 log10 (SD: 1.9) (t-Student; p=0.037)." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Number of patients \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Genotype \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">West European \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">North African \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Sub-Saharan \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">East European \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Asian \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">South American \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Viral load (log10) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">33 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">41 (80%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 (2%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 (5.9%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 (5.9%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 (5.9%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5.3 (SD: 2.3) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">B \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 (100%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6.7 (SD: 1.8) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 (11.1%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 (88.9%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5.6 (SD: 1.6) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">163 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">D \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">149 (91.4%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 (3.1%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 (4.9%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 (0.6%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.7 (SD: 1.8) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">E \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 (27.3%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 (72.7%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5.1 (SD: 2.2) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 (75%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 (25%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.3 (SD: 2.4) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">G \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 (100%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8.2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Viral load log10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.8 (SD: 2.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.5 (SD: 1.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.6 (SD: 2.0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.3 (SD: 2.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5.5 (SD: 2.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6.7 (SD: 2.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3692631.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Distribution of HBV genotypes and viral load based on the ethnicity of the patients." ] ] 4 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Parameter \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Number \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">cHR \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">95% CI \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">p value \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Age (absolute value) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.06 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.03–1.09 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.000 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Age (>45/<45 years) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5.83 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.10–16.13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.000 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Platelet (in thousand) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.98 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.97–0.99 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.000 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Platelet (<150×103/>150×103) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6.15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.58–14.63 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.000 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AST (absolute value) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.004 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.002–1.007 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.011 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ALT (absolute value) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.002 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.001–1.004 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.02 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GGT (absolute value) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.004 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.002–1.007 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.016 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Alkaline phosphatase (absolute value) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.007 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.005–1.01 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.000 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Alkaline phosphatase (>147/<147) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5.56 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.28–13.59 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Alfa-fetoprotein (absolute value) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.01 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.99–1.023 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N.S. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Alfa-fetoprotein (>5/<4.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7.14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.56–14.30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.000 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">INR (absolute value) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.03 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.008–1.055 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.05 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Glucose mg/dL (absolute value) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.01 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.006–1.02 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.007 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Glucose mg/dL (>123/<123) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.61 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.54–13.73 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.006 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bilirubin (absolute value) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.54 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.23–1.92 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.004 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Albumin (absolute value) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.71 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.36–1.40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N.S. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gamma globulins (>1.4/<1.39mg/dL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5.09 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.1–12.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.000 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Child (absolute value) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.08 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.50–2.88 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Child (value >5/=5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.52–27.24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.000 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ALBI (grade 2+3 vs. grade 1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.04 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.21–7.64 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.018 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gender (male/female) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13.29 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.78–99.11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.012 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Concomitant VHB-VHC/others \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5.43 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.10–14.04 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.000 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DNA-VHB >20,000/<20,000UI/mL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.42 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.32–8.83 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.011 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Elastometry (kPa absolute value) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">250 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.06 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.02–1.11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.016 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Elastometry (>10kPa/<10kPa) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">250 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">29.19 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.40–250.27 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.002 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IL28B genotype (TT/CC+CT) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">242 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5.38 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.08–26.73 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.04 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HBeag+/HBeAg− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.71 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.34–20.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N.S. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Heavy alcohol intake \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.932 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.25–8.41 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.015 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Antiviral treatment vs. no treated \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.95 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.83–4.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N.S. \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3692632.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Results of the univariate Cox analysis associated with the risk of developing liver complications during follow-up. Unadjusted hazard ratio values." ] ] 5 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Parameter \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Number \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">adHR \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">95% CI \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">p value \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Weight value \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Age (>45/<45 years) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.44–43.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.22 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Glycaemia >126/<125 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.24–13.67 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.026 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.09 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Coinfection VHB-VHC infection/others \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.06 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.19–13.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.012 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.07 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gender (male/female) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8.30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.07–64.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.04 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.19 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Alkaline phosphatase (>147/<147) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5.73 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.23–14.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.51 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Child (value >6/=5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.35 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.56–11.82 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.005 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.15 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DNA-VHB >4.3 log/<4.3 log \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.79 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.21–11.84 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.025 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.0 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3692630.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Independent factors were linked to the development of hepatocarcinoma. 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Prediction model of hepatocellular carcinoma development in chronic hepatitis B virus infection in Spanish cohort

Modelo de predicción del desarrollo de carcinoma hepatocelular en infección crónica por el virus de la hepatitis B en una cohorte española

Paula Gavilána, Juan-Carlos Gavilánb,c,

Corresponding author

jc_gavilan@hotmail.com

Corresponding author.

, Rocío Arnedob,c, Encarnación Clavijod, Isabel Vicianae, José-Antonio González-Correaa

a Universidad de Málaga, IBIMA-Plataforma BIONAND, Departamento de Farmacología y Pediatría, Facultad de Medicina, Campus de Teatinos s/n, 29071 Málaga, Spain

b Departamento de Medicina Interna, Hospital Universitario Virgen de la Victoria, Málaga, Spain

c Hospital Internacional Vithas Xanit, Benalmádena, Spain

d Universidad de Málaga, IBIMA-Plataforma BIONAND, Departamento de Microbiología, Facultad de Medicina, Campus de Teatinos s/n, 29071 Málaga, Spain

e Departamento de Microbiología, Hospital Universitario Virgen de la Victoria, Málaga, Spain

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        "titulo" => "Modelo de predicci&#243;n del desarrollo de carcinoma hepatocelular en infecci&#243;n cr&#243;nica por el virus de la hepatitis B en una cohorte espa&#241;ola"
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">The cumulated incidence of HCC throughout the follow-up in each of the risk groups established from the optimal cut-off point indicated for each score &#40;A&#58; HCCB&#59; B&#58; aMAP&#59; C&#58; PAGE-B&#59; D&#58; REACH-B&#41;&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Liver cancer is the seventh most prevalent cancer in 2020 worldwide and the third leading cause of cancer-related mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">1</span></a> Hepatocellular carcinoma &#40;HCC&#41; is the most common primary liver cancer&#44; with a higher incidence in patients with liver cirrhosis&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">2</span></a> Its distribution worldwide is heterogeneous and is related to the broad variability in the prevalence of the different risk factors associated with the development of the disease&#46; Chronic hepatitis B virus &#40;CHB&#41; infection remains the leading cause of HCC globally&#44; with areas of high incidence&#44; such as East Asia&#44; Micronesia&#44; Sub-Saharan Africa and Southeast Asia&#44; where age-specific rates range from 13&#46;3 to 17&#46;7<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>100&#44;000 inhabitants&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">This fact is closely related to the high prevalence of chronic B virus infection in the aforementioned areas &#40;prevalence rates ranged from 3&#46;5 to 7&#46;5&#37;&#41;&#46; In contrast to the incidence of HCC in Western Europe&#44; Mediterranean countries and North America with HCC age-specific incidence rates ranging from 5&#46;3 to 6&#46;8<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>100&#44;000 inhabitants in which the prevalence of chronic hepatitis B &#40;CHB&#41; ranged from 0&#46;5 to 1&#46;5&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">3</span></a> In addition to the development of established cirrhosis&#44; many other factors have been related to an increased risk of hepatocellular carcinoma in patients with chronic hepatitis B virus infection&#59; some of them are host-dependent as genetic factors&#44; male gender&#44;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">4</span></a> age&#44;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">5</span></a> liver steatosis&#44;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">6</span></a> diabetes<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">7</span></a> and alcohol intake&#44;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">8</span></a> and others depend on viral factors such as infection with positive HBeAg variants&#44;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">9</span></a> genotype and viral mutations&#44;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">10</span></a> coinfection with hepatitis C virus&#44;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">11</span></a> and degree of viral hepatitis B replication&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">12</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Antiviral treatment has enabled the inhibition of viral replication and has significantly attenuated necro-inflammation and resultant fibrosis in patients with chronic hepatitis B&#46; Nevertheless&#44; the risk of HCC is reduced but not eliminated in patients undergoing effective antiviral therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">13</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The annual incidence of HCC ranges from 0&#46;01&#37; to 5&#46;4&#37; in patients with chronic hepatitis B treated with antiviral&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">14</span></a> The success of treatment for HCC largely depends on the stage at which it is diagnosed&#44; with 5-year survival rates of 70&#8211;75&#37; if HCC is diagnosed at an early stage<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">15</span></a> and a survival time of 1 year or less if the diagnosis is made at an advanced stage&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">16</span></a> Therefore&#44; an effective and successful HCC surveillance program would offer early diagnosis and improve prognosis&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Nonetheless&#44; applying a standardized policy for antiviral therapy and HCC surveillance to all patients with chronic hepatitis B could be burdensome and not cost-effective&#46; Previous studies have shown that surveillance programs are considered cost-effective when the annual incidence of HCC exceeds 1&#8211;2&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">17</span></a> Thus&#44; stratification of the risk of HCC in chronic hepatitis B is helpful for proper management&#44; and it allows identification of high-risk groups&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Long-term screening in cohorts of patients with chronic HBV infection for the early diagnosis of liver cancer consumes time and healthcare resources&#46; Therefore&#44; it is important to identify those high-risk carriers in whom screening will be cost-effective&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The aim of the study is to identify clinical and viral factors linked to the development of hepatocarcinoma in an unselected cohort of European patients with chronic hepatitis B virus infection in southern Spain treated under the recommendations of the European Association for the Study of the Liver &#40;EASL&#41; and the American Association for the Study of Liver Diseases &#40;AASLD&#41;&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">This study aimed to develop a clinical score useful for the identification of high-risk patients&#44; which provides the opportunity to efficiently use clinical resources for early cancer detection in a cost-effective manner&#46; We checked the diagnostic accuracy of the developed score &#40;HCCB&#41; along with three of the main scores from different models that have proven to be useful for this purpose&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Material and methods</span><p id="par0045" class="elsevierStylePara elsevierViewall">A longitudinal cohort study with retrospective data review of 453 patients with chronic hepatitis B virus infection was conducted between January 1991 and December 2022 in the liver units of two Hospitals in M&#225;laga &#40;Spain&#41;&#46; Seven patients diagnosed with HCC during the first evaluation were excluded&#46; This study was approved by the ethics boards of both of the hospitals&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Demographic&#44; main biochemical and viral variables used in the statistical analysis were obtained in the initial evaluation of patients and collected retrospectively&#46; We reported viral loads in IU&#47;mL&#59; however&#44; for statistical analysis&#44; they were converted into log<span class="elsevierStyleInf">10</span> IU&#47;mL&#46; In patients whose viral load was below the detection limit &#40;15<span class="elsevierStyleHsp" style=""></span>IU&#47;mL&#41;&#44; this value was used for log<span class="elsevierStyleInf">10</span> transformation&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Successive clinical assessments were performed at 6-month intervals&#44; including alpha-fetoprotein and ultrasound checks&#46; Contrast-enhanced computed tomography &#40;CT&#41; or magnetic resonance imaging &#40;MRI&#41; was performed when a nodule suspected to be an HCC was detected on ultrasonography&#46; Nodules without typical imaging findings were analyzed using tumor biopsy&#46; HCC was diagnosed according to the criteria defined by the American Association for the Study of Liver Disease&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">18</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Authors declared that the research was conducted according to the principles of the World Medical Association Declaration of Helsinki &#8220;Ethical Principles for Medical Research Involving Human Subjects&#8221;&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Statistical analyses were performed using the Statistical Program for Social Sciences &#40;SPSS 20&#46;0 for Windows&#59; SPSS Inc&#46;&#44; Chicago&#44; IL&#44; USA&#41;&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">A Kaplan&#8211;Meier analysis was performed to obtain curves with a time-to-events method to determine the HCC incidence&#46; A Cox proportional hazard model was used to estimate the multivariable-adjusted hazard ratios&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">We performed a multivariate regression analysis in a non-automated manner until we reached a model with maximum predictability based on the Cox proportional risk model&#46; A previous assessment was performed to exclude multicollinearity between the predictor variables using an analysis of the variance inflation factor &#40;VIF&#41; and the maximum value of the condition index&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">The adjusted hazard ratio &#40;HR&#41; values were weighted to create a score to determine the risk of liver cancer &#40;HCCB&#41; and identify low and high-risk groups&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">The utilization of ROC curves and computation of the area under the curve &#40;AUROC&#41; enabled us to compare the predictive power of our score with three of the main models utilized in clinical practice to identify subgroups at high risk for HCC development&#44; named aMAP&#44;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">19</span></a> PAGE-B<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">20</span></a> and REACH-B&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">21</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Finally&#44; we analyzed the characteristics of the tests considered positive in the identification of the high-risk group for liver cancer and obtained them from the identification of the optimal cut-off point in the ROC curves of the four scores applied&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Results</span><p id="par0095" class="elsevierStylePara elsevierViewall">The initial evaluation of the original cohort revealed the presence of liver cancer in 7 of the 453 patients&#59; all of them were excluded from the study&#46; The remaining 446 patients &#40;280 males and 166 females&#41; were included in the study&#44; with a follow-up time ranging from 0&#46;5 to 31&#46;5 years &#40;mean&#58; 13&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>9&#46;5 years&#59; median&#58; 11&#46;4 years&#41;&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">The median age of the males was 44&#46;7 years &#40;SD&#58; 14&#46;5&#41; vs&#46; 42&#46;5 years &#40;SD&#58; 13&#46;9&#41; for females&#59; <span class="elsevierStyleItalic">p</span>&#58; 0&#46;015&#46; Infection with HBeAg negative hepatitis B virus occurred in 385 out of 446 patients &#40;86&#46;3&#37;&#41;&#46; HBeAg positive infection was more frequent in males &#40;OR&#58; 3&#46;97&#59; 95&#37; CI 1&#46;9&#8211;8&#46;3&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; and in patients with a risk of sexual exposition &#40;OR&#58; 3&#46;68&#59; 95&#37; CI 1&#46;98&#8211;6&#46;84&#41;&#59; they had a higher viral replication &#40;7&#46;17 log<span class="elsevierStyleInf">10</span> &#40;SD&#58; 1&#46;51&#41; vs&#46; 3&#46;37 log<span class="elsevierStyleInf">10</span> &#40;SD&#58; 1&#46;90&#41;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; and a higher prevalence of infection by genotypes other than D &#40;OR&#58; 3&#46;39&#59; 95&#37; CI 1&#46;75&#8211;6&#46;58&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; than those with the HBeAg negative variety&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">There was a concurrent infection with the hepatitis C virus in 29 patients &#40;6&#46;5&#37;&#41; and in 8 patients &#40;1&#46;8&#37;&#41; with Delta virus&#46; Coinfection with two or more hepatitis viruses was more frequent in men &#40;OR&#58; 2&#46;06&#59; 95&#37; CI 0&#46;95&#8211;4&#46;48&#59; <span class="elsevierStyleItalic">p</span>&#58; 0&#46;061&#41; and in patients with risk factors for parenteral exposure &#40;OR&#58; 12&#46;2&#59; 95&#37; CI 5&#46;9&#8211;25&#46;2&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; Patients with coinfection with other viruses had lower HBV viral replication compared with those with infection by HBV alone &#40;2&#46;70 log<span class="elsevierStyleInf">10</span> &#91;SD&#58; 2&#46;28&#93; vs&#46; 3&#46;99 log<span class="elsevierStyleInf">10</span> &#91;SD&#58; 2&#46;25&#93;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;002&#41;&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">The ethnicity of the patients in our cohort was mostly Western European &#40;81&#37;&#41;&#44; followed by African &#40;7&#46;3&#37;&#41;&#44; Eastern European &#40;6&#46;2&#37;&#41;&#44; Asian &#40;4&#46;6&#37;&#41; and South American patients &#40;0&#46;9&#37;&#41;&#46; European patients were older than non-Europeans &#40;46&#46;8 years &#91;SD&#58; 14&#46;7&#93; vs&#46; 36&#46;8 years &#91;SD&#58; 10&#46;7&#93;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">One hundred sixty patients &#40;36&#46;6&#37;&#41; received antiviral treatment&#58; 29 &#40;18&#46;1&#37;&#41; were treated with a temporary schedule of interferon&#44; and 150 &#40;81&#46;9&#37;&#41; were treated with nucleos&#40;t&#41;ide analogs with or without previous interferon treatment&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">The viral genotype could be identified in 245 patients &#40;54&#46;0&#37;&#41;&#46; The prevalence of the different genotypes and their peak viral loads according to the ethnic origin of the patients is described in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0125" class="elsevierStylePara elsevierViewall">Hepatocellular carcinoma &#40;HCC&#41; was detected in 21 of 446 patients &#40;4&#46;7&#37;&#41; along the follow-up with a global incidence density rate of 0&#46;33 tumors per 100 patients-year&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">The factors linked to the risk of liver cancer throughout the follow-up period were identified using bivariate Cox regression analysis and included classifying and continuous predictor variables&#46; Some of the latter&#44; such as age&#44; DNA-HBV levels&#44; or Child-P score&#44; were transformed into classifying variables with cut-off points chosen in relation to values of clinical and statistical significance published in previous studies&#46; The findings are outlined in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0135" class="elsevierStylePara elsevierViewall">Variables such as the IL28 B genotype &#40;TT vs&#46; CT and CC&#41; were statistically associated with an increased risk of HCC in the univariate analysis &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">This finding has already been described by some authors in the scientific literature&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">22</span></a> However&#44; it was not included in the multivariate analysis because it could only be tested in just over 58&#37; of the cohort&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Similarly&#44; we found a direct relationship between transient elastography values and HCC risk &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; However&#44; this parameter could only be tested in just over 50&#37; of the patients&#44; and in many of them&#44; it was performed during follow-up and not during the baseline assessment&#46; Therefore&#44; it was not included in the multivariate analysis&#46; For the same reason&#44; we did not test our cohort with models that included transient elastography in their scores&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">23</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">The variables included in the multivariate Cox regression analysis that behaved as independent factors associated with the development of HCC are shown in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0155" class="elsevierStylePara elsevierViewall">Factor&#39;s weights were taken as the corresponding estimated coefficients in Cox regression analysis after being divided by the smallest coefficient and rounded to the nearest integer&#46; The weighted adjustment of the hazard ratio values obtained in the multivariate analysis allowed the elaboration of a predictive score to assess the risk of HCC &#40;HCCB&#41;&#44; as follows&#58;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Child score &#40;1&#46;15 points if the value is 6 or higher&#59; 0 points if it is 5&#41;<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>gender &#40;2&#46;19 points for males&#59; 0 points for females&#41;<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>coinfection HBV-HCV &#40;1&#46;07 points for coinfection&#59; 0 points without coinfection&#41;<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>glucose values &#40;1&#46;09 points if it is above 126<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#41;<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>alkaline phosphatase &#40;1&#46;51 if the value is greater than 147<span class="elsevierStyleHsp" style=""></span>UI&#47;mL&#41;<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>Age &#40;3&#46;22 points for patients older than 45 years&#41;<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>DNA-VHB &#40;1 point if values are higher than 20&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;mL&#41;&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">The application of this score in our cohort obtained the following values&#58;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Minimum value&#58; 0 point&#59; maximum&#58; 10&#46;16&#46; Mean 3&#46;82&#46; 33rd percentile&#58; 3&#46;19&#46; 66th percentile&#58; 5&#46;41&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">The use of ROC curves and the determination of the area under the curve &#40;AUROC&#41; showed that the diagnostic accuracy to classify correctly patients for the HCCB score was 0&#46;878 &#40;95&#37; CI 0&#46;797&#8211;0&#46;959&#41;&#44; a value slightly higher than obtained for aMAP score&#58; 0&#46;753 &#40;95&#37; CI 0&#46;652&#8211;0&#46;853&#41;&#44; PAGE-B score&#58; 0&#46;773 &#40;95&#37; CI 0&#46;693&#8211;0&#46;854&#41;&#44; and REACH-B score&#58; 0&#46;730 &#40;95&#37; CI 0&#46;635&#8211;0&#46;826&#41; when they were applied to our cohort &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0180" class="elsevierStylePara elsevierViewall">The optimal cut-off point was estimated in the ROC curves for each of the models&#46; For the HCCB score&#44; the optimal cut-off value was chosen from the coordinates of the curve for a sensitivity value of 0&#46;905 and a 1<span class="elsevierStyleHsp" style=""></span>&#8722;<span class="elsevierStyleHsp" style=""></span>specificity value of 0&#46;406&#46; In the remaining scores&#44; the optimal cut-off point applied was the one described by the authors&#44; from which it was possible to differentiate the two risk groups for the development of HCC in the HBV cohort&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Using Kaplan&#8211;Meier analysis and applying the Log-Rank test&#44; we determined the cumulative incidence of HCC throughout the follow-up in each of the risk groups established from the optimal cut-off point indicated for each score&#46; These are represented in <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>A&#8211;D&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0190" class="elsevierStylePara elsevierViewall">A value greater than 5&#46;39 points was estimated as the cut-off limit for considering the diagnostic test as positive in the discrimination of patients with high and low risk for HCCB&#46; This high-risk group included 193 of the total of 446 patients &#40;43&#46;3&#37;&#41; and 19 of the 21 patients who developed HCC during the follow-up&#44; with an incidence density rate for this group of 1&#46;13 HCC per 100 patients per year&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">The low-risk group accounted for 253 of the total 446 patients &#40;56&#46;7&#37;&#41;&#46; Only two of the 21 patients who developed HCC &#40;9&#46;5&#37;&#41; belonged to this group&#44; with an incidence density rate of 0&#46;05 tumors per 100 patient per year&#44; significantly lower than the high-risk group &#40;Log-Rank <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>A shows the cumulative incidence of HCC among the high and low-risk groups estimated from the optimal cut-off point for the HCCB score&#44; as well as the number and percentage of patients in the cohort included in each of the risk groups&#44; which allows the estimation of the degree of efficiency of the model&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>B&#8211;D represents the cumulative incidence of HCC estimated from the optimal cut-off point for the high and low-risk groups for the aMAP score &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>B&#41;&#44; PAGE-B score &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>C&#41;&#44; and REACH-B score &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>D&#41;&#44; respectively&#46; These figures show the number of patients included in each risk group&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">In <a class="elsevierStyleCrossRef" href="#sec0060">supplementary material</a>&#44; we can observe the characteristic of the tests considered diagnostic for classifying high- and low-risk groups of HCC in our cohort based on the values of HCCB&#44; aMAP&#44; PAGE-B&#44; and REACH-B scores&#44; defined from the optimal cut-off point of the different ROC curves&#44; including the Youden index&#44; sensitivity&#44; specificity&#44; positive likelihood ratio&#44; and negative likelihood ratio&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">Finally&#44; we evaluated whether patients with a score greater than 5&#46;39 points on the HCCB were not only at a higher risk of developing HCC&#44; but also whether this fact has prognostic translation into complications or liver-related mortality&#46; To this end&#44; we analyzed a combined variable that included the development of complications due to portal hypertension&#44; need for liver transplantation&#44; or death from a hepatic cause&#46; The results are shown in <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Discussion</span><p id="par0220" class="elsevierStylePara elsevierViewall">Natural history studies in untreated patients have reported annual HCC incidences of 0&#46;3&#8211;0&#46;6&#37; in non-cirrhotic patients with CHB and 2&#46;2&#8211;3&#46;7&#37; in compensated cirrhotic patients&#44; with the highest rates observed in Asia&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">24</span></a></p><p id="par0225" class="elsevierStylePara elsevierViewall">In non-cirrhotic patients treated with entecavir or tenofovir&#44; annual HCC incidence ranges from 0&#46;0&#37; to 1&#46;4&#37; in Asian patients and from 0&#46;1&#37; to 1&#46;0&#37; in predominantly Caucasian populations&#46; In cirrhotic patients treated with entecavir or tenofovir&#44; HCC rates were approximately 4&#8211;5 times higher than in those without cirrhosis&#44; ranging from 0&#46;9&#37; to 5&#46;4&#37; in Asians and from 1&#46;5&#37; to 5&#46;2&#37; in Caucasians&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">14</span></a></p><p id="par0230" class="elsevierStylePara elsevierViewall">Based on this principle&#44; all patients with cirrhosis should be screened&#46; For patients without cirrhosis&#44; age&#44; sex&#44; race&#44; viral replication&#44; and family history can determine when and who should be screened&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">25</span></a></p><p id="par0235" class="elsevierStylePara elsevierViewall">Cohorts of patients with hepatitis B in western countries include patients with cirrhosis and chronic hepatitis with viral activity and variable degrees of fibrosis on antiviral treatment&#44; along with patients in stages in which current clinical guidelines do not contemplate antiviral treatment but in which other factors that do not depend on viral activity at the time of evaluation may have an impact on the risk of HCC&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">The inclusion of cirrhotic patients in the screening surveillance program for the early diagnosis of HCC was not questioned&#46; However&#44; the histological diagnostic reliability of cirrhosis is not always available&#44; and the diagnostic accuracy of elastography&#44; ultrasonography&#44; and panels are far from excellent and can be underestimated&#44; especially in the early stages&#46; Thus&#44; cirrhosis may be misclassified and further affect the performance of models containing cirrhosis as a predictor&#46; Therefore&#44; the clinical utility of these models in cirrhotic patients and the reason for not including them in the model are doubtful&#46; Some authors believe that future risk model studies should focus on non-cirrhotic patients&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">26</span></a></p><p id="par0245" class="elsevierStylePara elsevierViewall">Multivariate Cox regression includes variables commonly used in clinical practice that were significant in the univariate analyses&#44; which can be grouped as host-dependent factors &#40;sex and age&#41;&#44; virus-dependent factors &#40;pre-treatment peak viral load levels&#41;&#44; stages of liver function &#40;Child or ALBI&#41;&#44; and comorbidity &#40;coinfection with hepatitis C&#44; abusive alcohol intake or nonalcoholic steatosis&#41;&#46;</p><p id="par0250" class="elsevierStylePara elsevierViewall">Although not included in our model&#44; we consider that the baseline value of transient elastography could improve its predictive ability by facilitating the detection of cases with significant fibrosis in patients in the precirrhotic or early stages&#46; At the same time&#44; it could behave as a surrogate marker of factors possibly linked to the risk of HCC&#44; such as significant hepatic steatosis&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">27</span></a></p><p id="par0255" class="elsevierStylePara elsevierViewall">The results obtained from the four models tested in our cohort showed good discriminative accuracy in classifying patients into groups at high and low risk of developing HCC&#44; with AUROC ranging between 0&#46;87 for HCCB and 0&#46;73 for REACH-B&#46; The Youden index for the optimal cut-off point calculated in each of the models is shown as <a class="elsevierStyleCrossRef" href="#sec0060">supplementary material</a> and showed a higher value for HCCB&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall">The sensibility for positive tests obtained from the determination of the optimal cut-off point in the ROC curves is higher for HCCB and lower for REACH-B&#44; with a positive likelihood ratio ranging from 2&#46;83 for HCCB and 1&#46;70 for REACH-B&#44; which allows us to identify one HCC for every eight positive tests in our score compared to one in nine and a half&#44; ten and thirteen positive tests in aMAP&#44; PAGE-B and REACH-B&#44; respectively &#40;<a class="elsevierStyleCrossRef" href="#sec0060">supplementary material</a>&#41;&#46; The proportion of patients in the high-risk group ranged from 36&#46;3&#37; in the cohort for aMAP score to 49&#46;2&#37; for REACH-B &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>A&#8211;D&#41;&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">However&#44; the most important value when comparing different predictive models is a negative predictive value &#40;NPV&#41; for low-risk groups greater than 99&#37;&#44; as shown in the HCCB &#40;<a class="elsevierStyleCrossRef" href="#sec0060">supplementary material</a>&#41;&#46; It identifies a low-risk population with an incidence density of 0&#46;05 HCC&#47;100 person-years&#44; below the value of 0&#46;2&#37; considered cost-effective for non-cirrhotic patients&#44; corresponding to a percentage of 56&#46;7&#37; of the cohort&#44; in which the standard screening established in the guidelines could be questioned&#44; especially among patients without antiviral treatment&#44; circumstance previously pointed out by other authors&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">28</span></a></p><p id="par0270" class="elsevierStylePara elsevierViewall">Finally&#44; it should be noted that the proportion of patients receiving antiviral treatment was significantly higher in the high-risk group compared to the low-risk group &#40;51&#46;6&#37; vs&#46; 29&#46;6&#37;&#59; <span class="elsevierStyleItalic">p</span>&#58; 0&#46;001&#41;&#46; However&#44; 48&#46;9&#37; of the patients did not receive it because they did not meet the current clinical criteria for it&#46;</p><p id="par0275" class="elsevierStylePara elsevierViewall">The main weakness of our study is the absence of a cohort of validation to confirm the proper functioning of the score developed&#46; In the initial design&#44; we assessed the possibility of carrying out the study on a random sample of 75&#37; of our cohort and applying it to the rest&#46; But the number of patients made us give up on it&#46;</p><p id="par0280" class="elsevierStylePara elsevierViewall">Therefore&#44; the results obtained in our model must be validated in external cohorts of unselected Western patients undergoing treatment under conditions accepted in clinical guidelines&#44; in which the incidence of HCC is lower than that obtained in Asian or selected cohorts treated with antiviral agents&#46; In Western unselected cohorts&#44; additional factors associated with to HBV infection&#44; such as coinfection with other viruses&#44; alcohol consumption or prevalence of non-alcoholic steatosis linked to diabetes and obesity&#44; may play a pathogenic role in the risk of HCC development&#44; as well as in the older age of the patients due to different transmission mechanisms compared to the Asian population&#46;</p><p id="par0285" class="elsevierStylePara elsevierViewall">In any case&#44; we consider that the staging of HCC risk established by the model we describe&#44; or any other model&#44; should always be complementary to the consideration of the high risk of HCC after the diagnosis of liver cirrhosis&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">29</span></a></p><p id="par0290" class="elsevierStylePara elsevierViewall">Nonetheless&#44; the fact that HBV-associated HCC may also occur in non-cirrhotic livers&#44; suggests that in addition to stimulating host immune response and driving chronic necrotizing inflammation in the liver&#44; HBV also plays a direct role in liver transformation by triggering common and cause-specific oncogenic pathways&#44;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">30</span></a> and justifies the search for predictive risk models beyond the diagnosis of cirrhosis itself&#46;</p><p id="par0295" class="elsevierStylePara elsevierViewall">Finally&#44; given the evolving nature of the disease&#44; the risk assessment established by predictive models should be reassessed periodically&#44; possibly every ten years&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Ethical approval</span><p id="par0300" class="elsevierStylePara elsevierViewall">This study was approved by the Institutional Ethics Committee of both the hospitals in Malaga&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Funding</span><p id="par0305" class="elsevierStylePara elsevierViewall">None declared&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Authors&#8217; contributions</span><p id="par0310" class="elsevierStylePara elsevierViewall">Paula Gavil&#225;n Franco&#58; investigation&#44; writing of the original draft&#44; data analysis&#44; and visualization&#46; Juan Carlos Gavil&#225;n Carrasco&#58; conceptualization&#44; methodology&#44; software&#44; formal analysis&#44; project administration&#46; Roc&#237;o Arnedo&#58; writing review&#44; edition&#44; investigation&#46; Encarnaci&#243;n Clavijo and Isabel Viciana&#58; writing the review&#44; edition&#44; and investigation&#46; Jose Antonio Gonzalez Correa&#58; conceptualization&#44; writing review and supervision&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Informed consent</span><p id="par0315" class="elsevierStylePara elsevierViewall">Patient consent was waived due to the exemption authorized by both Ethics Committees because it was a retrospective study with a high number of patients and the data collected was anonymized&#46;</p><p id="par0320" class="elsevierStylePara elsevierViewall">Authors declared that the research was conducted according to the principles of the World Medical Association Declaration of Helsinki &#8220;Ethical Principles for Medical Research Involving Human Subjects&#8221;&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conflict of interest</span><p id="par0325" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Data availability</span><p id="par0330" class="elsevierStylePara elsevierViewall">No new data were created or analyzed in this study&#46; Data sharing was not applicable in this study&#46;</p></span></span>"
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            2 => "Prediction model of hepatocarcinoma development"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction and objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To identify risk factors associated with the development of hepatocellular carcinoma &#40;HCC&#41; in an unselected cohort of patients with chronic B virus infection &#40;CHB&#41; in Spain&#46; A predictive model was developed to assess the risk of HCC&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Material and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A prospective open-cohort study recruited 446 unselected patients with chronic hepatitis B infection from two hospitals in M&#225;laga &#40;Spain&#41;&#46; The follow-up time ranged from 0&#46;5 to 31&#46;5 years &#40;mean&#58; 13&#46;8&#59; SD&#58; 9&#46;5&#59; median&#58; 11&#46;4 years&#41;&#46; We used a Cox proportional hazard model to estimate the multivariable-adjusted hazard ratios of risk factors associated with the development of liver cancer and developed a clinical score&#44; &#40;HCCB score&#41; to determine the risk of liver cancer&#44; that categories patients into two risk levels for the development of HCC&#46; We compared the diagnostic accuracy of our model with other previously published&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">During the follow-up period&#44; 4&#46;80&#37; of the patients developed liver cancer &#40;21 out of 437&#41;&#44; 0&#46;33 cases per 100 patient-years&#46; Multivariate Cox regression analysis revealed that age &#62;45 years&#44; male gender&#44; hepatitis C coinfection&#44; alkaline phosphatase &#62;147<span class="elsevierStyleHsp" style=""></span>IU&#47;L&#44; Child score &#62;5 points&#44; glucose &#62;126<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#44; and a viral load &#62;4&#46;3 log<span class="elsevierStyleInf">10</span> IU&#47;mL were independent risk factors&#46; A risk score has been developed with a high predictive capacity for identifying patients at high risk of developing hepatocellular carcinoma&#46; AUROC 0&#46;87 &#40;95&#37; CI&#58; 0&#46;79&#8211;0&#46;95&#41;&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">An HCCB score greater than 5&#46;42 points identifies a subgroup of chronic hepatitis B patients at high risk of developing liver cancer&#44; who could benefit from screening measures for the early diagnosis of HCC&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Antecedentes y objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Identificar loa factores de riesgo asociados al desarrollo de carcinoma hepatocelular &#40;CHC&#41; en una cohorte no seleccionada de pacientes con infecci&#243;n cr&#243;nica por virus de la hepatitis B en Espa&#241;a&#46; Desarrollo de un modelo predictivo para evaluar el riesgo de desarrollo de hepatocarcinoma&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Materiales y m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Se trata de un estudio prospectivo de cohortes abiertas donde se reclut&#243; a 446 pacientes no seleccionados con infecci&#243;n cr&#243;nica por hepatitis B en 2 hospitales de M&#225;laga &#40;Espa&#241;a&#41;&#46; El tiempo de seguimiento oscil&#243; entre 0&#44;5 y 31&#44;5 a&#241;os &#40;media&#58; 13&#44;8&#59; DE&#58; 9&#44;5&#59; mediana&#58; 11&#44;4 a&#241;os&#41;&#46; Utilizamos un modelo de riesgos proporcionales de Cox para estimar los cocientes de riesgos ajustados para m&#250;ltiples variables de los factores de riesgo asociados con el desarrollo de c&#225;ncer hep&#225;tico y desarrollamos un <span class="elsevierStyleItalic">score</span> cl&#237;nico &#40;HCCB&#41; para determinar el riesgo de desarrollo de hepatocarcinoma&#44; que clasifica a los pacientes en 2 niveles de riesgo para su desarrollo&#46; Comparamos la precisi&#243;n diagn&#243;stica de nuestro modelo con otros publicados previamente&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Durante el seguimiento&#44; el 4&#44;80&#37; de los pacientes desarrollaron hepatocarcinoma &#40;21 de 437&#41;&#59; 0&#44;33 casos por 100 pacientes&#47;a&#241;o&#46; El an&#225;lisis multivariante de regresi&#243;n de Cox revel&#243; que la edad &#62;45 a&#241;os&#44; el sexo masculino&#44; la coinfecci&#243;n por hepatitis C&#44; la fosfatasa alcalina &#62;147<span class="elsevierStyleHsp" style=""></span>UI&#47;l&#44; la puntuaci&#243;n Child &#62;5 puntos&#44; la glucosa &#62;126<span class="elsevierStyleHsp" style=""></span>mg&#47;dl y una carga viral &#62;4&#44;3<span class="elsevierStyleHsp" style=""></span>Log10<span class="elsevierStyleHsp" style=""></span>UI&#47;ml eran factores de riesgo independientes&#46; Desarrollamos un <span class="elsevierStyleItalic">score</span> con una alta capacidad predictiva para identificar a los pacientes con alto riesgo de desarrollar CHC&#46; AUROC&#58; 0&#44;87&#59; IC 95&#37;&#58; 0&#44;79-0&#44;95&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Una puntuaci&#243;n HCCB superior a 5&#44;42 puntos identifica a un subgrupo de pacientes con hepatitis B cr&#243;nica con alto riesgo de desarrollar CHC&#44; que podr&#237;an beneficiarse de medidas de cribado para el diagn&#243;stico precoz del mismo&#46;</p></span>"
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            "apendice" => "<p id="par0340" class="elsevierStylePara elsevierViewall">The following are the supplementary data to this article&#58;<elsevierMultimedia ident="upi0005"></elsevierMultimedia></p>"
            "etiqueta" => "Appendix B"
            "titulo" => "Supplementary data"
            "identificador" => "sec0060"
          ]
        ]
      ]
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      0 => array:7 [
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        "mostrarFloat" => true
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          0 => array:4 [
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">COR curve graphic setting the accuracy diagnosis of HCCB score to correctly classify patients at risk of HCC obtained from our cohort&#44; as well as the curves obtained by applying three of the most used hepatocarcinoma predictive scores of HCC risk &#40;aMAP&#44; PAGE-B and REACH-B&#41;&#46; It represents the area under curve &#40;AUROC&#41; for the four indicators with their confidence&#39;s intervals&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Fig&#46; 2"
        "tipo" => "MULTIMEDIAFIGURA"
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">The cumulated incidence of HCC throughout the follow-up in each of the risk groups established from the optimal cut-off point indicated for each score &#40;A&#58; HCCB&#59; B&#58; aMAP&#59; C&#58; PAGE-B&#59; D&#58; REACH-B&#41;&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "fig0015"
        "etiqueta" => "Fig&#46; 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">This figure shows the differences in the survival curves for HCCB risk groups in the hepatitis B cohort&#44; with a statistically worse prognosis for the combined prognostic variable in the high-risk group &#40;HCCB score &#62;5&#46;39&#41; vs&#46; low-intermediate risk group &#40;HCCB score &#60;5&#46;39&#41;&#46;</p>"
        ]
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          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Asians and South Americans had higher viral loads compared to the others &#40;ANOVA&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;003&#41;&#46;</p><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Viral load log<span class="elsevierStyleInf">10</span> genotypes B<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>C &#40;Asian patients&#41; were significantly higher than others&#58; 6&#46;0 log<span class="elsevierStyleInf">10</span> &#40;SD&#58; 1&#46;8&#41; vs&#46; 4&#46;9 log<span class="elsevierStyleInf">10</span> &#40;SD&#58; 1&#46;9&#41; &#40;<span class="elsevierStyleItalic">t</span>-Student&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;037&#41;&#46;</p>"
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                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;25&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;3 &#40;SD&#58; 2&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Viral load log<span class="elsevierStyleInf">10</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;8 &#40;SD&#58; 2&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;5 &#40;SD&#58; 1&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">3&#46;6 &#40;SD&#58; 2&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">3&#46;3 &#40;SD&#58; 2&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;5 &#40;SD&#58; 2&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;7 &#40;SD&#58; 2&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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        "descripcion" => array:1 [
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                0 => """
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Parameter&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span> value&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Age &#40;absolute value&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">446&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;06&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;03&#8211;1&#46;09&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;0&#46;000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Age &#40;&#62;45&#47;&#60;45 years&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">446&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">2&#46;10&#8211;16&#46;13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;0&#46;000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Platelet &#40;in thousand&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">446&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;98&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;97&#8211;0&#46;99&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;0&#46;000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Platelet &#40;&#60;150<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">3</span>&#47;&#62;150<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">3</span>&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">446&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;15&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">2&#46;58&#8211;14&#46;63&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;0&#46;000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AST &#40;absolute value&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">446&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;004&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;002&#8211;1&#46;007&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;011&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ALT &#40;absolute value&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">446&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;002&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;001&#8211;1&#46;004&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;02&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">GGT &#40;absolute value&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">446&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;004&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;002&#8211;1&#46;007&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;016&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alkaline phosphatase &#40;absolute value&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">446&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;007&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;005&#8211;1&#46;01&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;0&#46;000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alkaline phosphatase &#40;&#62;147&#47;&#60;147&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">446&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;56&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;28&#8211;13&#46;59&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alfa-fetoprotein &#40;absolute value&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">446&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;01&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;99&#8211;1&#46;023&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#46;S&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alfa-fetoprotein &#40;&#62;5&#47;&#60;4&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">446&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#46;14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;56&#8211;14&#46;30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;0&#46;000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">INR &#40;absolute value&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">446&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;03&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;008&#8211;1&#46;055&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;05&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Glucose mg&#47;dL &#40;absolute value&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">446&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;01&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;006&#8211;1&#46;02&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;0&#46;007&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Glucose mg&#47;dL &#40;&#62;123&#47;&#60;123&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">446&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;61&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;54&#8211;13&#46;73&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;006&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bilirubin &#40;absolute value&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">446&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;54&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;23&#8211;1&#46;92&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;0&#46;004&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Albumin &#40;absolute value&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">446&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;71&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;36&#8211;1&#46;40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#46;S&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Gamma globulins &#40;&#62;1&#46;4&#47;&#60;1&#46;39<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">446&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;09&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;1&#8211;12&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;0&#46;000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Child &#40;absolute value&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">446&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;08&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;50&#8211;2&#46;88&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Child &#40;value &#62;5&#47;&#61;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">446&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;52&#8211;27&#46;24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;0&#46;000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ALBI &#40;grade 2<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>3 vs&#46; grade 1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">446&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;04&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;21&#8211;7&#46;64&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;018&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Gender &#40;male&#47;female&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">446&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13&#46;29&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;78&#8211;99&#46;11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;012&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Concomitant VHB-VHC&#47;others&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">446&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;43&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;10&#8211;14&#46;04&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;0&#46;000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">DNA-VHB &#62;20&#44;000&#47;&#60;20&#44;000<span class="elsevierStyleHsp" style=""></span>UI&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">446&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;42&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;32&#8211;8&#46;83&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;011&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Elastometry &#40;kPa absolute value&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">250&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;06&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;02&#8211;1&#46;11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;016&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Elastometry &#40;&#62;10<span class="elsevierStyleHsp" style=""></span>kPa&#47;&#60;10<span class="elsevierStyleHsp" style=""></span>kPa&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">250&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">29&#46;19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;40&#8211;250&#46;27&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;002&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IL28B genotype &#40;TT&#47;CC<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>CT&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">242&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;38&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;08&#8211;26&#46;73&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;04&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HBeag&#43;&#47;HBeAg&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">446&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;71&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;34&#8211;20&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#46;S&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Heavy alcohol intake&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">446&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;932&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">1&#46;25&#8211;8&#46;41&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Antiviral treatment vs&#46; no treated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">446&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">1&#46;95&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;83&#8211;4&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#46;S&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Parameter&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Number&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">adHR&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">95&#37; CI&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span> value&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Weight value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Age &#40;&#62;45&#47;&#60;45 years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">446&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;44&#8211;43&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;0&#46;000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Glycaemia &#62;126&#47;&#60;125&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">446&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;24&#8211;13&#46;67&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;026&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;09&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Coinfection VHB-VHC infection&#47;others&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">446&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;06&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;19&#8211;13&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;012&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;07&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Gender &#40;male&#47;female&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">446&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
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