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External validation of the PAGE-B score for HCC risk prediction in people living with HIV/HBV coinfection

Open AccessPublished:January 20, 2023DOI:https://doi.org/10.1016/j.jhep.2022.12.029

      Highlights

      • This external validation study included 2963 individuals with HIV/HBV coinfection from 4 European cohorts.
      • Within a median of 9.6 years, 68 patients developed hepatocellular carcinoma (incidence rate 2.58/1000 person-years).
      • Among individuals with HIV/HBV coinfection, PAGE-B (based on age, sex and platelets) showed good model discrimination.
      • A PAGE-B score <10 had a negative predictive value of 99.4% for developing hepatocellular carcinoma within 5 years.

      Abstract

      Background & Aims

      Hepatitis B virus (HBV) coinfection is common among people living with HIV (PLWH) and the most important cause of hepatocellular carcinoma (HCC). Whereas risk prediction tools for HCC exist for patients with HBV monoinfection, they have not been evaluated in PLWH. We performed an external validation of PAGE-B in people with HIV/HBV coinfection.

      Methods

      We included PLWH with a positive HBsAg and without HCC before starting tenofovir from four European cohorts, and estimated the predictive performance of PAGE-B on HCC occurrence over 15 years of tenofovir-containing antiretroviral therapy (ART). Model discrimination was assessed after multiple imputation using Cox regression with the prognostic index as covariate, and by calculating Harrell’s c-index. Calibration was assessed by comparing cumulative incidences with the PAGE-B derivation study using Kaplan-Meier curves.

      Results

      In total, 2’963 individuals with HIV/HBV coinfection on tenofovir-containing ART were included. PAGE-B was <10 in 26.5%, 10–17 in 57.7%, and ≥18 in 15.7% of patients. Within a median follow-up of 9.6 years, HCC occurred in 68 individuals (2.58/1000 patient-years, 95% confidence interval [CI] 2.03–3.27). The regression slope of the prognostic index for developing HCC within 15 years was 0.93 (95% CI 0.61–1.25), and the pooled c-index was 0.77 (range 0.73–0.80), both indicating good model discrimination. Cumulative incidence of HCC was lower in our study compared to the derivation study. A PAGE-B cut-off of <10 had a negative predictive value for developing HCC within 5 years of 99.4%. Restricting efforts to individuals with a PAGE-B of ≥10 would spare HCC screening in 27% of individuals.

      Conclusions

      For individuals with HIV/HBV coinfection, PAGE-B is a valid tool to determine the need for HCC screening.

      IMPACT AND IMPLICATIONS

      Chronic hepatitis B virus (HBV) infection is the most important cause of hepatocellular carcinoma (HCC) among people living with HIV, and valid risk prediction may guide HCC screening efforts to high-risk individuals. We aimed at validating PAGE-B, a risk prediction tool that is based on age, gender, and platelets, among 2963 individuals with HIV/HBV coinfection who received tenofovir-containing antiretroviral therapy. In the present study, PAGE-B showed good discrimination, adequate calibration, and a cut-off of less than 10 had a negative predictive value for developing HCC within 5 years of 99.4%. These results indicate that PAGE-B is a simple and valid risk prediction tool to determine the need for HCC screening among people living with HIV and HBV.

      Graphical abstract

      Keywords

      Potential conflicts of interest

      BS reports support to his institution for advisory boards and travel grants from Gilead Sciences and ViiV, outside of the present work. AM has received honoraria, travel support, lecture fees and/or consultancy fees from ViiV, Gilead and Eiland and Bonnin. MvdV reports support to his institution for advisory boards and unrestricted research grants from Gilead Sciences, Merck and ViiV. FB has received travel grants and honoraria from ViiV Healthcare, Gilead, ViiV, Janssen, and MSD, and support for attending meetings from Gilead, Janssen, MSD, and ViiV Healthcare. JKR reports honoraria for himself for advisory boards or DSMB participation and speaking at educational events from Abivax, Galapagos, Gilead Sciences, Janssen, Merck, Theratechnologies and ViiV, outside of the submitted work. HFG has received unrestricted research grants from Gilead Sciences; fees for data and safety monitoring board membership from Merck; consulting/advisory board membership fees from Gilead Sciences, Merck, Johnson and Johnson, Novartis and ViiV Healthcare; and grants from the Swiss National Science Foundation, the Yvonne Jacob Foundation and from National Institutes of Health. AR reports support to his institution for advisory boards and/or travel grants from MSD, Gilead Sciences, Pfizer and Abbvie, and an investigator-initiated trial (IIT) grant from Gilead Sciences. All remuneration went to his home institution and not to AR personally, and all remuneration was provided outside the submitted work. GW reports unrestricted research grants from Gilead Sciences and Roche Diagnostics, as well as travel grants and advisory board/lecture fees from ViiV, Gilead Sciences and MSD, all paid to his institution. All other authors declare no conflicts of interest.

      Funding

      EuroSIDA was supported by the European Union’s Seventh Framework Programme for research, technological development and demonstration under EuroCoord grant agreement #260694. Current support includes unrestricted grants by ViiV Healthcare LLC, GlaxoSmithKline R&D Limited, Janssen Scientific Affairs, Janssen R&D, Bristol-Myers Squibb Company, Merck Sharp & Dohme Corp, Gilead Sciences. The participation of centres from Switzerland was supported by The Swiss National Science Foundation (Grant #148522 and #201369). The study is also supported by the Danish National Research Foundation (Grant #DNRF126) and by the International Cohort Consortium of Infectious Disease (RESPOND).
      The ATHENA cohort is managed by Stichting HIV Monitoring and supported by a grant from the Dutch Ministry of Health, Welfare and Sport through the Centre for Infectious Disease Control of the National Institute for Public Health and the Environment.
      The ANRS CO3 Aquitaine-AquiVIH-NA cohort is supported by the ANRS│MIE and the CHU de Bordeaux.
      This study has been financed within the framework of the Swiss HIV Cohort Study, supported by the Swiss National Science Foundation (Grant #148522 and #201369), by SHCS project #751 and by the SHCS research foundation. The SHCS data are gathered by the Five Swiss University Hospitals, two Cantonal Hospitals, 15 affiliated hospitals and 36 private physicians (listed in http://www.shcs.ch/180-health-care-providershttp://www.shcs.ch/180-health-care-providers). Further funding was obtained from the NEAT-ID Foundation. GW was supported by a Professorship (PP00P3_176944) from the Swiss National Science Foundation. BS was supported by an institutional research grant (CTU Grant). The funders had no role in the study design, data collection, analysis, and decision to publish.

      Authors’ contribution

      BS, AR and GW conceived and designed the study. BS performed the statistical analyses with help from MR and AL. BS and GW wrote the first draft of the manuscript. All authors contributed to the acquisition and interpretation of the data, critically revised the manuscript, and approved its final version.

      Data availability statement

      Data are available upon reasonable request. The data sets generated and/or analyzed during the current study are not publicly available, since they are subject to national data protection laws and restrictions imposed by the ethics committee to ensure data privacy of the study participants. The code for the analysis is archived at https://doi.org/10.5281/zenodo.7466614.

      Introduction

      Between 5 and 15% of people living with HIV (PLWH) also have a chronic hepatitis B virus (HBV) infection, the single most important cause of end-stage liver disease and hepatocellular carcinoma (HCC) worldwide [
      • Perz J.F.
      • Armstrong G.L.
      • Farrington L.A.
      • Hutin Y.J.F.
      • Bell B.P.
      The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide.
      ]. Screening individuals with HBV infection and a high risk for HCC using ultrasound every 6 months is recommended to detect cancers at an early and curable stage [
      • Kanwal F.
      • Singal A.G.
      Surveillance for Hepatocellular Carcinoma: Current Best Practice and Future Direction.
      ,
      • Costentin C.E.
      • Layese R.
      • Bourcier V.
      • Cagnot C.
      • Marcellin P.
      • Guyader D.
      • et al.
      Compliance With Hepatocellular Carcinoma Surveillance Guidelines Associated With Increased Lead-Time Adjusted Survival of Patients With Compensated Viral Cirrhosis: A Multi-Center Cohort Study.
      ]. However, screening uptake remains suboptimal, and therefore represents a missed opportunity to prevent HCC-related deaths [
      • Willemse S.
      • Smit C.
      • Sogni P.
      • Sarcletti M.
      • Uberti-Foppa C.
      • Wittkop L.
      • et al.
      Low compliance with hepatocellular carcinoma screening guidelines in hepatitis B/C virus co-infected HIV patients with cirrhosis.
      ,
      • Patel N.
      • Post F.A.
      Surveillance for hepatocellular carcinoma in people of African ancestry with HIV and Hepatitis B.
      ]. We previously showed that among individuals with HIV and HBV, those who were older than 46 years or had liver cirrhosis had the highest risk of developing HCC [
      • Wandeler G.
      • Mauron E.
      • Atkinson A.
      • Dufour J.-F.
      • Kraus D.
      • Reiss P.
      • et al.
      Incidence of hepatocellular carcinoma in HIV/HBV-coinfected patients on tenofovir therapy: Relevance for screening strategies.
      ]. To guide clinicians in deciding whether a patient needs HCC screening or not, simple HCC risk prediction tools could help with risk stratification.
      PAGE-B, a prognostic score including age, sex and platelet count at initiation of antiviral therapy, was derived from a multi-country study of 1’815 European individuals with HBV mono-infection, and reliably predicted their 5-year HCC risk [
      • Papatheodoridis G.
      • Dalekos G.
      • Sypsa V.
      • Yurdaydin C.
      • Buti M.
      • Goulis J.
      • et al.
      PAGE-B predicts the risk of developing hepatocellular carcinoma in Caucasians with chronic hepatitis B on 5-year antiviral therapy.
      ]. As the score is based on inexpensive and readily available measurements that do not include the evaluation of cirrhosis, PAGE-B has become an established tool for clinicians to discuss HCC screening with patients, including in settings with limited access to liver biopsy or transient elastography (TE) [
      European Association for the Study of the Liver (EASL)
      Clinical Practice Guidelines on the management of hepatitis B virus infection.
      ]. The use of PAGE-B is also suggested by the European AIDS Clinical Society guidelines to assess the HCC risk in individuals with HIV/HBV coinfection [

      European AIDS Clinical Society (EACS). Guidelines for the management of people living with HIV 2021. https://www.eacsociety.org/media/final2021eacsguidelinesv11.0_oct2021.pdf (accessed February 25, 2022).

      ], despite the lack of evaluation of its predictive value in this population. The validity of this score in PLWH is challenged by differences in HCC incidence, the presence of HIV-induced thrombocytopenia and the high prevalence of additional HCC risk factors such as hepatitis C virus (HCV) and hepatitis delta virus (HDV) infections, as well as alcohol use [
      • Wandeler G.
      • Mauron E.
      • Atkinson A.
      • Dufour J.-F.
      • Kraus D.
      • Reiss P.
      • et al.
      Incidence of hepatocellular carcinoma in HIV/HBV-coinfected patients on tenofovir therapy: Relevance for screening strategies.
      ].
      To provide scientific evidence for HCC surveillance recommendations, we conducted an external validation of the prognostic performance of the PAGE-B score in persons living with HIV and HBV from a large cohort collaboration in Europe.

      Patients and methods

      Study setting and participants

      We considered participants with HBV from four prospective longitudinal cohorts: the Swiss HIV Cohort Study (SHCS) [
      • Scherrer A.U.
      • Traytel A.
      • Braun D.L.
      • Calmy A.
      • Battegay M.
      • Cavassini M.
      • et al.
      Cohort Profile Update: The Swiss HIV Cohort Study (SHCS).
      ], the AIDS Therapy Evaluation in the Netherlands (ATHENA) Cohort [
      • Boender T.S.
      • Smit C.
      • van Sighem A.
      • Bezemer D.
      • Ester C.J.
      • Zaheri S.
      • et al.
      AIDS Therapy Evaluation in the Netherlands (ATHENA) national observational HIV cohort: cohort profile.
      ], the Agence Nationale de Recherches sur le Sida (ANRS) CO3 Aquitaine Cohort-AQUIVIH-NA (Aquitaine) [
      • Collin A.
      • Le Marec F.
      • Vandenhende M.-A.
      • Lazaro E.
      • Duffau P.
      • Cazanave C.
      • et al.
      Incidence and Risk Factors for Severe Bacterial Infections in People Living with HIV. ANRS CO3 Aquitaine Cohort, 2000-2012.
      ], and EuroSIDA [
      • Laut K.
      • Kirk O.
      • Rockstroh J.
      • Phillips A.
      • Ledergerber B.
      • Gatell J.
      • et al.
      The EuroSIDA study: 25 years of scientific achievements.
      ]. Laboratory values as well as sociodemographic and clinical data are prospectively recorded using standardized protocols. All study sites’ ethical committees approved the cohort studies, and all patients provided written or verbal informed consent according to local regulations. The study is presented following the TRIPOD statement [
      • Collins G.S.
      • Reitsma J.B.
      • Altman D.G.
      • Moons K.G.M.
      Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD): the TRIPOD statement.
      ].
      We included all PLWH with a positive HBsAg test before starting an antiretroviral therapy (ART) regimen including tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF). Patients who developed HCC prior to the start of tenofovir, and those without follow-up data available after this date were excluded. Differences in study eligibility between the original PAGE-B derivation study among people with HBV monoinfection [
      • Papatheodoridis G.
      • Dalekos G.
      • Sypsa V.
      • Yurdaydin C.
      • Buti M.
      • Goulis J.
      • et al.
      PAGE-B predicts the risk of developing hepatocellular carcinoma in Caucasians with chronic hepatitis B on 5-year antiviral therapy.
      ] and the present validation study are shown in Table S1. Unlike in the derivation study, individuals of African or Asian origin and those with known HCV or HDV coinfection were included in our main analysis. Follow-up was measured from tenofovir start until the earliest of HCC diagnosis, death, loss to follow-up, last follow-up visit, or database closure (01.12.2020 for SHCS and ATHENA, 01.01.2021 for EuroSIDA, and 01.01.2022 for Aquitaine). Patients who stopped tenofovir during follow-up remained included in all analyses.

      Outcomes and definitions

      We aimed to estimate the predictive performance of the PAGE-B score on the occurrence of HCC. Whereas PAGE-B was derived to predict the 5-year risk of HCC, we assessed its performance within the full follow-up period of our study population (15 years). Information on HCC diagnosis was prospectively collected from all cohorts with standardized case-report forms, using hospital discharge reports, imaging studies and liver histology reports to verify the diagnosis. The choice of whether and how HCC screening was performed was left to the discretion of the treating physician. In accordance with the original publication, the PAGE-B score was calculated based on values for sex, age, and platelet categories (≥200 G/L, 100-199 G/L, <100 G/L). Liver cirrhosis was defined as Metavir stage F4 on liver biopsy or liver stiffness >11 kPa in TE at any time-point. If neither of these measurements was available, we used the AST to platelet ratio index (APRI) >2.0 at the time of tenofovir start to indicate cirrhosis. Coinfection with HCV was defined as a positive HCV-RNA prior to tenofovir start, and HDV coinfection was defined as having a positive anti-HDV serology at any time point since cohort registration.

      Statistical Analyses

      Cumulative incidence of HCC stratified by the same PAGE-B categories as in the original derivation study (<10, 10-17, ≥18) was presented using Kaplan Meier curves [
      • Papatheodoridis G.
      • Dalekos G.
      • Sypsa V.
      • Yurdaydin C.
      • Buti M.
      • Goulis J.
      • et al.
      PAGE-B predicts the risk of developing hepatocellular carcinoma in Caucasians with chronic hepatitis B on 5-year antiviral therapy.
      ]. The predictive performance of the PAGE-B score during follow-up was assessed using discrimination and calibration, as recommended by Royston and Altman [
      • Royston P.
      • Altman D.G.
      External validation of a Cox prognostic model: principles and methods.
      ]. Observation time was right-censored at 15 years to limit the excess influence of individuals with longer follow-up. To assess model discrimination, we first calculated the prognostic index using the linear predictor based on the regression coefficients of the PAGE-B model (Fig. S1). We then fitted a Cox regression model with the prognostic index as a covariate, where a slope <1 indicates poorer discrimination compared to the original study, and >1 indicates better discrimination. We further measured discrimination using Harrell’s c-index, which gives the proportion of patients where predictions and outcomes are concordant, and is equivalent to the area under the receiver operating curve. Calibration was assessed by comparing cumulative incidence estimates, calculated using the Kaplan-Meier method, between the present validation and the original validation study. Screening for HCC is considered effective if the yearly risk is above 0.2% (equal to 3% in 15 years assuming a stable risk per year) [
      • Heimbach J.K.
      • Kulik L.M.
      • Finn R.S.
      • Sirlin C.B.
      • Abecassis M.M.
      • Roberts L.R.
      • et al.
      AASLD guidelines for the treatment of hepatocellular carcinoma.
      ]. To calculate the PAGE-B cut-off that reflects a risk above that threshold, we calculated cumulative incidence of HCC within 15 years using the Kaplan-Meier method. Sensitivity, specificity, negative and positive predictive values at 5 years (as in the original derivation study) were calculated from a time-dependent ROC curve analysis using the timeROC package [
      • Blanche P.
      • Dartigues J.-F.
      • Jacqmin-Gadda H.
      Estimating and comparing time-dependent areas under receiver operating characteristic curves for censored event times with competing risks.
      ].
      As information on platelets at tenofovir start was missing in 36% of patients, model validation was performed after multiple imputation of predictors. Assuming missingness at random, we performed multivariable imputation by chained equations using the mice package [
      • van Buuren S.
      • Groothuis-Oudshoorn K.
      mice: Multivariate Imputation by Chained Equations in R.
      ]. The variables used for the multiple imputation model were the outcome (HCC) and 19 covariates (Table S2). The distribution of imputed platelet values is shown in Fig. S2. After imputing 50 datasets, all calculations were performed individually on each dataset, and estimates were combined using Rubin’s rules [

      Rubin DB. Multiple Imputation for Nonresponse in Surveys. Wiley; 1987. https://doi.org/10.1002/9780470316696.

      ] or by providing the median and the range of values (c-index) [
      • Marshall A.
      • Altman D.G.
      • Holder R.L.
      • Royston P.
      Combining estimates of interest in prognostic modelling studies after multiple imputation: current practice and guidelines.
      ]. All analyses were performed using R, version 4.1.3 [

      R Core Team. R: A Language and Environment for Statistical Computing 2022. https://www.R-project.org/(accessed April 4, 2022).

      ,
      • Wickham H.
      • Averick M.
      • Bryan J.
      • Chang W.
      • McGowan L.
      • François R.
      • et al.
      Welcome to the tidyverse.
      ].

      Sensitivity Analyses

      To evaluate the robustness of our results, we performed five types of sensitivity analyses. First, we repeated the analyses censoring all individuals at five years after tenofovir start as done in the derivation study. Second, we evaluated the robustness of the multiple imputation process comparing the results with complete case analyses. Third, we excluded individuals of African origin in accordance with the derivation study, as HCC seem to occur at a younger age in this population compared to individuals of non-African origin [
      • Yang J.D.
      • Gyedu A.
      • Afihene M.Y.
      • Duduyemi B.M.
      • Micah E.
      • Kingham T.P.
      • et al.
      Hepatocellular Carcinoma Occurs at an Earlier Age in Africans, Particularly in Association With Chronic Hepatitis B.
      ]. Fourth, we explored the possibility of immortal time bias as some individuals started tenofovir prior to registration in the cohorts. Therefore, we repeated the analyses restricted to individuals who started tenofovir after cohort registration and performed analyses where baseline was defined as the start of tenofovir if this date was after cohort registration, and as cohort registration date otherwise. Finally, we performed a sensitivity analysis excluding all individuals known to be coinfected with HDV or HCV.

      Results

      Study population

      Of 2’988 eligible patients with the last HBsAg prior to tenofovir start being positive, we excluded 10 patients who developed HCC before starting tenofovir, and 15 patients without available follow-up data after tenofovir start, resulting in a study population of 2’963 patients (Fig. S3). The ATHENA cohort followed the largest proportion of patients (n = 1319, 44.5%), followed by EuroSIDA (800, 27.0%), the SHCS (507, 17.1%) and the Aquitaine cohort (337, 11.4%). At tenofovir start, the median age was 41 years (interquartile range [IQR] 35 to 47 years), 466 (16%) participants were female, 2’023 (68%) were Caucasian, and 314 (11%) had evidence of liver cirrhosis (48.4% diagnosed with TE, 39.8% with APRI, and 11.8% with liver biopsy). Although most patient characteristics were similar across cohorts, the amount of missing data on platelets and HDV coinfection varied markedly (Table 1). Compared to the original PAGE-B derivation study [
      • Papatheodoridis G.
      • Dalekos G.
      • Sypsa V.
      • Yurdaydin C.
      • Buti M.
      • Goulis J.
      • et al.
      PAGE-B predicts the risk of developing hepatocellular carcinoma in Caucasians with chronic hepatitis B on 5-year antiviral therapy.
      ], individuals in the current validation study were younger (median age 41 years in our study vs. 52 years in the derivation study), more likely to be male (84% vs. 70%), had a lower median body mass index (22.8 vs. 26.1 kg/m2), and more commonly received other nucleoside analogues prior to tenofovir (55% vs. 33%), whereas the median platelet count was similar in both studies (190 vs. 191 G/L, Table S3).
      Table 1Patient characteristics at tenofovir start, stratified by cohort.
      CharacteristicOverall (n = 2963)Aquitaine (n = 337)ATHENA (n = 1319)EuroSIDA (n = 800)SHCS (n = 507)
      Male sex2477 (84%)277 (82%)1147 (87%)662 (83%)391 (77%)
      Age in years (IQR)41 (35 to 47)42 (37 to 48)41 (35 to 48)41 (36 to 47)40 (35 to 46)
      Caucasian2023 (68%)289 (86%)774 (59%)641 (80%)319 (63%)
       (Missing)69 (2.3%)3 (0.9%)8 (0.6%)58 (7.2%)0 (0%)
      Region of Origin
       European or USA2023 (68%)289 (86%)774 (59%)641 (80%)319 (63%)
       African525 (18%)41 (12%)293 (22%)56 (7.0%)135 (27%)
       Latin American162 (5.5%)1 (0.3%)148 (11%)0 (0%)13 (2.6%)
       Asian155 (5.2%)3 (0.9%)96 (7.3%)18 (2.2%)38 (7.5%)
       Other29 (1.0%)0 (0%)0 (0%)27 (3.4%)2 (0.4%)
       Unknown69 (2.3%)3 (0.9%)8 (0.6%)58 (7.2%)0 (0%)
      Transmission Group
       MSM1536 (52%)159 (49%)820 (67%)330 (41%)227 (47%)
       PWID412 (14%)62 (19%)41 (3.3%)234 (29%)75 (15%)
       Heterosexual783 (26%)98 (30%)350 (29%)156 (20%)179 (37%)
       Other50 (1.7%)8 (2.4%)16 (1.3%)19 (2.4%)7 (1.4%)
       (Missing)182 (6.1%)10 (3.0%)92 (7.0%)61 (7.6%)19 (3.7%)
      HIV Viral Load
       ≥ 200 cp/mL1596 (54%)146 (43%)780 (59%)382 (48%)288 (57%)
       50 – 199 cp/mL190 (6.5%)21 (6.2%)88 (6.7%)57 (7.1%)24 (4.7%)
       Below 50 cp/mL1018 (34%)112 (33%)419 (32%)298 (37%)189 (37%)
       (Missing)159 (5.4%)58 (17%)32 (2.4%)63 (7.9%)6 (1.2%)
      BMI in kg/m222.8 (20.8 to 25.1)22.3 (20.4 to 24.6)22.9 (20.9 to 25.0)22.7 (20.8 to 25.1)23.0 (20.8 to 25.8)
       (Missing)639 (22%)92 (27%)185 (14%)317 (40%)45 (8.9%)
      CD4 cell count, cells/μL (IQR)323 (182 to 510)376 (196 to 584)310 (170 to 490)346 (210 to 531)314 (198 to 472)
       (Missing)181 (6.1%)60 (18%)32 (2.4%)83 (10%)6 (1.2%)
      Diabetes183 (6.2%)38 (11%)82 (6.2%)39 (4.9%)24 (4.7%)
      Liver cirrhosis314 (11%)27 (9.9%)129 (15%)94 (12%)64 (16%)
      ALT at baseline in IU/L (IQR)41 (25 to 79)38 (24 to 70)47 (26 to 134)39 (25 to 69)39 (25 to 65)
       (Missing)731 (25%)60 (18%)444 (34%)191 (24%)36 (7.1%)
      Platelets in G/L (IQR)190 (141 to 236)194 (144 to 235)188 (133 to 235)192 (152 to 233)190 (148 to 239)
       (Missing)1063 (36%)76 (23%)560 (42%)406 (51%)21 (4.1%)
      Platelet count category
       ≥ 200 G/L859 (25%)121 (36%)347 (26%)175 (22%)216 (43%)
       100-199 G/L828 (28%)102 (30%)325 (25%)179 (22%)222 (46%)
       <100 G/L213 (7.2%)38 (11%)87 (6.6%)40 (5%)48 (9.5%)
       (Missing)1063 (36%)76 (23%)560 (42%)406 (51%)21 (4.1%)
      HDV coinfection147 (5%)15 (17%)13 (9.4%)69 (8.6%)50 (11%)
       (Missing)1941 (66%)250 (74%)1180 (89%)451 (56%)60 (12%)
      HCV coinfection274 (9.2%)22 (6.5%)51 (3.9%)157 (20%)44 (8.7%)
      HBeAg-positivity799 (27%)106 (50%)515 (45%)26 (3.2%)152 (55%)
       (Missing)1277 (43%)124 (37%)167 (13%)756 (94%)230 (45%)
      XTC use before TFV1629 (55%)211 (63%)584 (44%)550 (69%)284 (56%)
      Prior XTC in years (IQR)3.7 (0.0 to 8.2)3.8 (0.0 to 7.2)0.0 (0.0 to 6.0)5.2 (0.0 to 8.1)9.9 (5.2 to 15.1)
      Follow-up on TFV in years (IQR)9.6 (4.9 to 13.3)10.8 (5.6 to 15.0)9.7 (5.3 to 13.1)8.4 (3.8 to 12.3)10.3 (5.2 to 14.3)
      IQR = interquartile range, MSM = men who have sex with men, PWID = persons who inject drugs, XTC = lamivudine or emtricitabine, TFV = tenofovir, HDV = hepatitis D virus, BMI = body mass index, HCV = hepatitis C virus, APRI = AST to platelet ratio index, ALT = alanine aminotransferase.

      Occurrence of HCC

      Within a median follow-up of 9.6 years (IQR 4.9 to 13.3 years), HCC was diagnosed in 68 individuals (2.3%, incidence rate 2.58 per 1’000 patient-years, 95% CI 2.03 to 3.27). Overall, 24 HCC (35.3%) occurred in ATHENA, 17 (25.0%) in EuroSIDA, 16 (23.5%) in the SHCS, and 13 (19.1%) in the Aquitaine cohort. Within 5 years of follow-up – the observation period used in the PAGE-B derivation study – HCC occurred in 36 individuals (1.2%, incidence rate 2.82 per 1’000 patient-years, 95% CI 2.03 to 3.91). The cumulative incidence was 0.28% at 1 year, 0.96% at 3 years, 1.39% at 5 years, 2.42% at 10 years, and 3.93% at 15 years. Of all patients who developed HCC, 90% were male, 81% were Caucasian, and 51 individuals died (overall survival rate 25%), with a median survival after HCC diagnosis of 11.7 months (95% CI 5.9 to 19.2).

      PAGE-B model validation

      For 1’890 individuals (63.8%), a PAGE-B score at the time of tenofovir start could be calculated based on complete case data. The distributions of PAGE-B values were similar in the complete case and imputation datasets (Figure 1A and 1C). In the complete case dataset, the PAGE-B score was <10 in 522 (27.6%), between 10 and 17 in 1’068 (56.5%), and ≥18 in 300 individuals (15.9%). After multiple imputation, 785 individuals (26.5%) had a score <10, 1711 (57.7%) had a score between 10 and 17, and 466 (15.7%) had a score ≥18. Thirty-nine HCC cases (55.7%) occurred in individuals with a PAGE-B of 18 or higher, 27 (38.6%) occurred in individuals with a PAGE-B between 10 and 17, whereas only 4 (5.7%) individuals with a PAGE-B score <10 developed an HCC (Figure 1B and 1D). Of 4 individuals with an HCC and a PAGE-B score <10, the median age was 37 years, 3 were of African and one was of Asian origin, one individual had evidence of liver cirrhosis on TE, and another individual had coinfection with HDV.
      Figure thumbnail gr1
      Figure 1Distribution of PAGE-B scores and hepatocellular carcinoma cases
      Distribution of available PAGE-B scores in the complete case data (A) and after multiple imputation (C). Hepatocellular carcinoma cases by PAGE-B score are represented as dots in the complete case data (B) and after multiple imputation (D).
      The regression slope of the prognostic index for the development of HCC within 15 years after tenofovir start was 0.93 (95% CI 0.61 to 1.25). This value was close to 1.0 (p-value = 0.67) and indicated preserved discrimination compared to the derivation study. Similarly, PAGE-B showed good discrimination with a pooled c-index of 0.77 (range 0.73 to 0.80), which was close to the results after internal (c-index: 0.81) and external (c-index: 0.82) validation performed in the original PAGE-B derivation study [
      • Papatheodoridis G.
      • Dalekos G.
      • Sypsa V.
      • Yurdaydin C.
      • Buti M.
      • Goulis J.
      • et al.
      PAGE-B predicts the risk of developing hepatocellular carcinoma in Caucasians with chronic hepatitis B on 5-year antiviral therapy.
      ]. Visual inspection of the Kaplan-Meier curves showed that the highest cumulative incidence of HCC was in individuals with a PAGE-B ≥18, followed by those with a PAGE-B between 10 and 17, whereas the lowest incidence was seen in individuals with a PAGE-B <10 (Figure 2A). Model calibration was assessed by comparing the cumulative incidence of HCC from our study with the results of the derivation study. The cumulative incidence of HCC over five years was 5.6% in individuals with a PAGE-B score ≥18 in our study compared to 17% in the derivation study. We also found a lower cumulative incidence in individuals with a PAGE-B score between 10 and 17 compared to the derivation study and this difference was observed throughout the full follow-up time (Table 2).
      Figure thumbnail gr2
      Figure 2Cumulative incidence of hepatocellular carcinoma since tenofovir start
      The Kaplan-Meier curves show the cumulative incidence of developing hepatocellular carcinoma (HCC) after starting tenofovir in the full study population (A, n = 2963) and after excluding individuals of African origin (B, n = 2438).
      Table 2Life table comparison of hepatocellular carcinoma (HCC) cases in the present study and the original derivation study.
      PAGE-B CategoryYearsN at riskCumulative N (Cumulative Incidence) of HCCsCumulative Incidence of Original Publication
      Papatheodoridis G et al. PAGE-B predicts the risk of developing hepatocellular carcinoma in Caucasians with chronic hepatitis B on 5-year antiviral therapy. J Hepatol 2016; 64:800–806.
      Complete caseImputationComplete caseImputationDerivationValidation
      Score <1014807341 (0.2%)1 (0.1%)0%0%
      24496941 (0.2%)1 (0.1%)0%0%
      34126511 (0.2%)1 (0.1%)0%0%
      53575732 (0.5%)2 (0.3%)0%0%
      102163582 (0.5%)2 (0.3%)n.r.n.r.
      15791314 (2.5%)4 (1.5%)n.r.n.r.
      Score 10-171100116251 (0.1%)1 (0.1%)0%0%
      293715343 (0.3%8 (0.5%)1%1%
      387714425 (0.5%)10 (0.6%)1%1%
      579413198 (0.9%)14 (0.9%)3%4%
      1049086313 (1.6%)21 (1.5%)n.r.n.r.
      1514727915 (2.2%)26 (2.3%)n.r.n.r.
      Score ≥1812684265 (1.8%)6 (1.4%)3%3%
      22473968 (2.9%)9 (2.1%)6%5%
      321735612 (4.6%)15 (3.7%)9%8%
      518531114 (5.6%)20 (5.2%)17%16%
      109217522 (11.2%)32 (10.1%)n.r.n.r.
      15285224 (14.4%)38 (16.0%)n.r.n.r.
      N = Number, HCC = hepatocellular carcinoma, n.r. = not reported.
      a Papatheodoridis G et al. PAGE-B predicts the risk of developing hepatocellular carcinoma in Caucasians with chronic hepatitis B on 5-year antiviral therapy. J Hepatol 2016; 64:800–806.
      Of 2438 non-African participants, 61 developed HCC: 37 (60.7%) had a PAGE-B ≥18, 23 (37.7%) had a PAGE-B between 10 and 17, and only one individual (1.6%) had a PAGE-B <10. HCC incidence rates between individuals of African (2.03 per 1’000 patient-years, 95% CI 1.06 to 3.90) and of non-African origin (2.69 per 1’000 patient-years, 95% CI 2.08 - 3.47) did not differ significantly (p = 0.43). The regression slope was 1.17 (0.78 to 1.56), the pooled c-index 0.80 (range 0.76 to 0.82), and the Kaplan-Meier curves confirmed good model discrimination (Figure 2B).

      Sensitivity analyses

      As the derivation study evaluated the PAGE-B score for the prediction of HCC within five years of tenofovir start, we repeated the analyses censoring all individuals at five years. The results remained largely unchanged, with a regression slope of 0.87 (95% CI 0.47 to 1.28) and a pooled c-index of 0.76 (range 0.71 to 0.79). Likewise, complete case analyses evaluating the HCC risk within the full follow-up period revealed similar results (regression slope 0.88, 95% CI 0.56 to 1.21; c-index 0.77, 95% CI 0.68 to 0.85). Results remained unchanged when we restricted analyses to individuals who started tenofovir after cohort registration (regression slope 0.94, 95% CI 0.58 to 1.30, c-index 0.77, range 0.72 to 0.80), and when we used cohort registration as baseline for individuals who started tenofovir prior to that date (regression slope 1.01, 95% CI 0.69 to 1.33, c-index 0.78, range 0.74 to 0.81). Similarly, excluding 382 individuals who were known to have HCV or HDV coinfection did not change the interpretation of our results (regression slope 0.89, 95% CI 0.55 to 1.23, c-index 0.76, range 0.74 to 0.79).

      Screening cut-off

      The cumulative incidence of HCC within the full follow-up period for each PAGE-B score is shown in Figure 3. The upper limit of the 95% confidence interval of the cumulative HCC risk was above the accepted screening threshold (HCC risk of 0.2% per year) for a PAGE-B score of >12 in the full dataset, and >13 after excluding individuals of African origin. Using a cut-off of >10 as in the original derivation study [
      • Papatheodoridis G.
      • Dalekos G.
      • Sypsa V.
      • Yurdaydin C.
      • Buti M.
      • Goulis J.
      • et al.
      PAGE-B predicts the risk of developing hepatocellular carcinoma in Caucasians with chronic hepatitis B on 5-year antiviral therapy.
      ], the sensitivity and specificity for developing HCC within five years of tenofovir start were 81.0% and 42.9%, respectively (negative predictive value 99.4%, Table S4). After excluding individuals of African origin, the sensitivity of a cut-off of >10 improved to 93.6% (negative predictive value 99.8%, Fig. S4). When increasing the cut-off to >12 in the full dataset, sensitivity was 77.7%, specificity was 51.8%, and the negative predictive value was 99.4%.
      Figure thumbnail gr3
      Figure 3Fifteen-year probability of developing hepatocellular carcinoma, by PAGE-B score
      Probability (solid line) and 95% confidence interval (shaded area) of developing hepatocellular carcinoma (HCC) within 15 years after tenofovir start in the full study population (A) and after excluding individuals of African origin (B). The dotted red line indicates the commonly accepted screening threshold (HCC risk of 0.2% per year). The upper limit of the 95% confidence interval for individuals with a PAGE-B score of 12 (full dataset) or 13 (non-African individuals) remains just under the accepted screening threshold.

      Discussion

      In this external validation study, the PAGE-B score showed good accuracy in predicting the HCC risk in a large collaboration of European cohorts of individuals living with HIV and HBV infection. Similar to the original derivation study [
      • Papatheodoridis G.
      • Dalekos G.
      • Sypsa V.
      • Yurdaydin C.
      • Buti M.
      • Goulis J.
      • et al.
      PAGE-B predicts the risk of developing hepatocellular carcinoma in Caucasians with chronic hepatitis B on 5-year antiviral therapy.
      ], individuals with a score below 10 were at very low risk of HCC, with a negative predictive value above 99%, confirming the usefulness of PAGE-B to target HCC surveillance efforts in individuals with HIV/HBV coinfection. In the subset of participants with a low PAGE-B score, 3 of 4 HCC cases occurred in individuals of African origin.
      Current guidelines suggest that individuals with HBV monoinfection and a PAGE-B score <10 do not need HCC screening because of a very low risk of HCC [
      European Association for the Study of the Liver
      EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma.
      ]. In the original derivation study, a score of <10 had a negative predictive value of 100%, meaning that no patient experienced HCC below that cut-off [
      • Papatheodoridis G.
      • Dalekos G.
      • Sypsa V.
      • Yurdaydin C.
      • Buti M.
      • Goulis J.
      • et al.
      PAGE-B predicts the risk of developing hepatocellular carcinoma in Caucasians with chronic hepatitis B on 5-year antiviral therapy.
      ]. We found a slightly lower negative predictive value of 99.4% in the full study population, and 99.8% after excluding individuals of African origin. These estimates are in line with the findings of previous PAGE-B external validation studies in individuals with HBV mono-infection [
      • Brouwer W.P.
      • van der Meer A.J.P.
      • Boonstra A.
      • Plompen E.P.C.
      • Pas S.D.
      • de Knegt R.J.
      • et al.
      Prediction of long-term clinical outcome in a diverse chronic hepatitis B population: Role of the PAGE-B score.
      ,
      • Kim M.N.
      • Hwang S.G.
      • Rim K.S.
      • Kim B.K.
      • Park J.Y.
      • Kim D.Y.
      • et al.
      Validation of PAGE-B model in Asian chronic hepatitis B patients receiving entecavir or tenofovir.
      ]. Although the risk for HCC with a score <10 was not 0% in our study, the yearly risk for HCC was below the recommended threshold of 0.2%, and therefore it seems justified to apply the same cut-offs to individuals with and without HIV coinfection. Since 27% of individuals in our study had a PAGE-B <10, targeting screening efforts to individuals with a PAGE-B of 10 and higher would substantially reduce the need for HCC surveillance. Based on our results, even a higher threshold of <12 could be considered, as the yearly HCC risk remained below 0.2% in those individuals, which would spare HCC screening in 473 (16%) additional individuals. However, the potential benefits of using a higher PAGE-B score cut-off than in the original derivation study need to be confirmed in other cohorts of individuals with HIV/HBV coinfection.
      In our study, PAGE-B model discrimination was similar to the original derivation study [
      • Papatheodoridis G.
      • Dalekos G.
      • Sypsa V.
      • Yurdaydin C.
      • Buti M.
      • Goulis J.
      • et al.
      PAGE-B predicts the risk of developing hepatocellular carcinoma in Caucasians with chronic hepatitis B on 5-year antiviral therapy.
      ] and comparable to other external validation studies performed among individuals with HBV monoinfection in Europe and Asia [
      • Brouwer W.P.
      • van der Meer A.J.P.
      • Boonstra A.
      • Plompen E.P.C.
      • Pas S.D.
      • de Knegt R.J.
      • et al.
      Prediction of long-term clinical outcome in a diverse chronic hepatitis B population: Role of the PAGE-B score.
      ,
      • Yip T.C.-F.
      • Wong G.L.-H.
      • Wong V.W.-S.
      • Tse Y.-K.
      • Liang L.Y.
      • Hui V.W.-K.
      • et al.
      Reassessing the accuracy of PAGE-B-related scores to predict hepatocellular carcinoma development in patients with chronic hepatitis B.
      ]. Our incidence of HCC was comparable to other cohorts of Caucasian participants with HIV/HBV coinfection [
      • Kim H.N.
      • Newcomb C.W.
      • Carbonari D.M.
      • Roy J.A.
      • Torgersen J.
      • Althoff K.N.
      • et al.
      Risk of HCC With Hepatitis B Viremia Among HIV/HBV-Coinfected Persons in North America.
      ], but markedly lower than in the original derivation study across all PAGE-B categories, leading to differences in model calibration. These discrepancies were most likely driven by differences in how HBV infection was defined across studies: To be included in the derivation study, individuals needed to have confirmed HBsAg positivity for at least 6 months, increased transaminases, and an HBV-DNA above 2000 IU/mL, in line with current HBV treatment guidelines [
      • Papatheodoridis G.
      • Dalekos G.
      • Sypsa V.
      • Yurdaydin C.
      • Buti M.
      • Goulis J.
      • et al.
      PAGE-B predicts the risk of developing hepatocellular carcinoma in Caucasians with chronic hepatitis B on 5-year antiviral therapy.
      ,
      European Association for the Study of the Liver (EASL)
      Clinical Practice Guidelines on the management of hepatitis B virus infection.
      ]. In our study, we considered every participant with a positive HBsAg prior to tenofovir start irrespective of whether they had evidence of liver inflammation, since tenofovir-containing ART is recommended in all individuals with HIV/HBV coinfection [

      European AIDS Clinical Society (EACS). Guidelines for the management of people living with HIV 2021. https://www.eacsociety.org/media/final2021eacsguidelinesv11.0_oct2021.pdf (accessed February 25, 2022).

      ]. Therefore, our study population was more likely to include participants with no or mild liver disease than the derivation study, which is also reflected by the lower prevalence of liver cirrhosis compared to the HBV monoinfection cohorts [
      • Kim M.N.
      • Hwang S.G.
      • Rim K.S.
      • Kim B.K.
      • Park J.Y.
      • Kim D.Y.
      • et al.
      Validation of PAGE-B model in Asian chronic hepatitis B patients receiving entecavir or tenofovir.
      ]. In addition, the lower HCC incidence observed in our study may also have been influenced by the higher proportion of individuals with HBV-active treatment prior to tenofovir start (55%) compared to the derivation study (33%).
      Although several models were developed to predict HCC in individuals with chronic HBV infection, PAGE-B remains the only score that has been validated for Caucasian patients. In contrast to the original PAGE-B derivation study, which was restricted to Caucasian individuals, we included all ethnic groups as PAGE-B has shown to perform well in individuals of Asian descent [
      • Kim M.N.
      • Hwang S.G.
      • Rim K.S.
      • Kim B.K.
      • Park J.Y.
      • Kim D.Y.
      • et al.
      Validation of PAGE-B model in Asian chronic hepatitis B patients receiving entecavir or tenofovir.
      ]. However, no study has evaluated its predictive performance among African individuals. In our study, most individuals with a low PAGE-B who developed HCC in our study were of African origin. As our analyses only included a small number of individuals of African origin, the predictive performance of PAGE-B in that population remains to be determined. As HCC may develop at a younger age in that population compared to non-African individuals [
      • Yang J.D.
      • Gyedu A.
      • Afihene M.Y.
      • Duduyemi B.M.
      • Micah E.
      • Kingham T.P.
      • et al.
      Hepatocellular Carcinoma Occurs at an Earlier Age in Africans, Particularly in Association With Chronic Hepatitis B.
      ,
      • Yang J.D.
      • Altekruse S.F.
      • Nguyen M.H.
      • Gores G.J.
      • Roberts L.R.
      Impact of country of birth on age at the time of diagnosis of hepatocellular carcinoma in the United States.
      ,
      • Yang J.D.
      • Mohamed E.A.
      • Aziz A.O.A.
      • Shousha H.I.
      • Hashem M.B.
      • Nabeel M.M.
      • et al.
      Characteristics, management, and outcomes of patients with hepatocellular carcinoma in Africa: a multicountry observational study from the Africa Liver Cancer Consortium.
      ], and age being an important component of PAGE-B, other risk stratification tools may be needed to guide surveillance efforts for that population.
      We present the first external validation of an HCC risk prediction model in a multinational population of individuals living with HIV and HBV, providing robust evidence for the current recommendation by the European AIDS Clinical Society guidelines to use PAGE-B for HCC risk stratification [

      European AIDS Clinical Society (EACS). Guidelines for the management of people living with HIV 2021. https://www.eacsociety.org/media/final2021eacsguidelinesv11.0_oct2021.pdf (accessed February 25, 2022).

      ]. However, despite our best efforts to pool data from large European cohorts, the statistical power of our study was limited, since a minimum of one hundred events is commonly suggested for external validation studies [
      • Collins G.S.
      • Ogundimu E.O.
      • Altman D.G.
      Sample size considerations for the external validation of a multivariable prognostic model: a resampling study.
      ]. Furthermore, the proportion of participants with missing platelet measurements was high, exceeding 50% in one cohort. Although we used multiple imputation and confirmed its robustness by comparing results from imputed with complete case data, some bias in the estimates of model performance cannot be excluded. In addition, information on HDV coinfection was limited in most cohorts. Since HDV acts as an additional risk factor for HCC [
      • Béguelin C.
      • Moradpour D.
      • Sahli R.
      • Suter-Riniker F.
      • Lüthi A.
      • Cavassini M.
      • et al.
      Hepatitis delta-associated mortality in HIV/HBV-coinfected patients.
      ], restricting our analyses to patients without HDV coinfection might have led to better model performance. Finally, participants in our collaboration of real-life cohorts underwent HCC screening according to the judgement of their treating physician. As individuals that clinicians perceived to be at higher risk may have been more likely to receive ultrasound examinations, the lack of systematic screening may have introduced the potential for detection bias.
      In conclusion, our results confirm that PAGE-B is a simple and valid risk prediction tool to determine the need for HCC screening among people living with HIV and HBV. Better risk prediction has the potential to increase surveillance uptake in high-risk individuals, as well as to reduce healthcare costs by avoiding screening of individuals with a very low HCC risk. Although PAGE-B performs well in most populations, better risk prediction models are urgently needed to inform surveillance strategies in individuals of African origin.

      Acknowledgments

      The authors thank all patients, physicians and nurses associated with the participating cohorts.
      Members of the Swiss HIV Cohort Study (SHCS).
      Abela I, Aebi-Popp K, Anagnostopoulos A, Battegay M, Bernasconi E, Braun DL, Bucher HC, Calmy A, Cavassini M, Ciuffi A, Dollenmaier G, Egger M, Elzi L, Fehr J, Fellay J, Furrer H, Fux CA, Günthard HF (President of the SHCS), Hachfeld A, Haerry D (deputy of "Positive Council"), Hasse B, Hirsch HH, Hoffmann M, Hösli I, Huber M, Jackson-Perry D (patient representatives), Kahlert CR (Chairman of the Mother & Child Substudy), Kaiser L, Keiser O, Klimkait T, Kouyos RD, Kovari H, Kusejko K (Head of Data Centre), Labhardt N, Leuzinger K, Martinez de Tejada B, Marzolini C, Metzner KJ, Müller N, Nemeth J, Nicca D, Notter J, Paioni P, Pantaleo G, Perreau M, Rauch A (Chairman of the Scientific Board), Salazar-Vizcaya L, Schmid P, Speck R, Stöckle M (Chairman of the Clinical and Laboratory Committee), Tarr P, Trkola A, Wandeler G, Weisser M, Yerly S.
      The multi-centre study group, EuroSIDA (national coordinators in parenthesis).
      Albania: (A Harxhi), University Hospital Center of Tirana, Tirana.
      Argentina: (M Losso), M Kundro, Hospital JM Ramos Mejia, Buenos Aires.
      Austria: (B Schmied), Klinik Penzing, Vienna; R Zangerle, Medical University Innsbruck, Innsbruck.
      Belarus: (I Karpov), A Vassilenko, Belarusian State Medical University, Minsk; VM Mitsura, Gomel State Medical University, Gomel; D Paduto, Regional AIDS Centre, Svetlogorsk.
      Belgium: (N Clumeck), S De Wit, M Delforge, Saint-Pierre Hospital, Brussels; E Florence, Institute of Tropical Medicine, Antwerp; L Vandekerckhove, University Ziekenhuis Gent, Gent.
      Bosnia-Herzegovina: (V Hadziosmanovic), Klinicki Centar Univerziteta Sarajevo, Sarajevo.
      Croatia: (J Begovac), University Hospital of Infectious Diseases, Zagreb.
      Czech Republic: (L Machala), D Jilich, Faculty Hospital Bulovka, Prague; D Sedlacek, Charles University Hospital, Plzen.
      Denmark: G Kronborg, T Benfield, Hvidovre Hospital, Copenhagen; J Gerstoft, O Kirk, Rigshospitalet, Copenhagen; C Pedersen, IS Johansen, Odense University Hospital, Odense; L Ostergaard, Skejby Hospital, Aarhus, L Wiese, Sjællands Universitetshospital, Roskilde; L N Nielsen, Hillerod Hospital, Hillerod.
      Estonia: (K Zilmer), West-Tallinn Central Hospital, Tallinn; Jelena Smidt, Nakkusosakond Siseklinik, Kohtla-Järve.
      Finland: (I Aho), Helsinki University Hospital, Helsinki.
      France: (J-P Viard), Hôtel-Dieu, Paris; K Lacombe, Hospital Saint-Antoine, Paris; C Pradier, E Fontas, Hôpital de l'Archet, Nice; C Duvivier, Hôpital Necker-Enfants Malades, Paris.
      Germany: (J Rockstroh), Universitäts Klinik Bonn; O Degen, University Medical Center Hamburg-Eppendorf, Infectious Diseases Unit, Hamburg; C Hoffmann, HJ Stellbrink, ICH Study Center GmbH & Co. KG, Hamburg; C Stefan, JW Goethe University Hospital, Frankfurt; J Bogner, Medizinische Poliklinik, Munich; G. Fätkenheuer, Universität Köln, Cologne.
      Georgia: (N Chkhartishvili) Infectious Diseases, AIDS & Clinical Immunology Research Center, Tbilisi.
      Greece: (H Sambatakou), Ippokration General Hospital, Athens; G Adamis, N Paissios, Athens General Hospital "G Gennimatas", Athens.
      Hungary: (J Szlávik), South-Pest Hospital Centre – National Institute for Infectology and Haematology, Budapest.
      Iceland: (M Gottfredsson), Landspitali University Hospital, Reykjavik.
      Ireland: (E Devitt), St. James's Hospital, Dublin.
      Israel: (L Tau), D Turner, M Burke, Ichilov Hospital, Tel Aviv; E Shahar, LM Wattad, Rambam Health Care Campus, Haifa; H Elinav, M Haouzi, Hadassah University Hospital, Jerusalem; D Elbirt, AIDS Center (Neve Or), Rehovot.
      Italy: (A D’Arminio Monforte), Istituto Di Clinica Malattie Infettive e Tropicale, Milan; G Guaraldi, R Esposito, I Mazeu, C Mussini, Università Modena, Modena; F Mazzotta, A Gabbuti, Ospedale S Maria Annunziata, Firenze; A Lazzarin, A Castagna, N Gianotti, Ospedale San Raffaele, Milan; M Galli, A Ridolfo, Osp. L. Sacco, Milan.
      Lithuania: (V Uzdaviniene) Vilnius University Hospital Santaros Klinikos, Vilnius; R Matulionyte, Vilnius University, Faculty of Medicine, Department of Infectious Diseases and Dermatovenerology, Vilnius.
      Luxembourg: (T Staub), R Hemmer, Centre Hospitalier, Luxembourg.
      Netherlands: (Marc vd Valk), Academisch Medisch Centrum bij de Universiteit van Amsterdam, Amsterdam.
      North Macedonia (J Trajanovska), University Clinic for Infectious Diseases & Febrile Conditions, Mother Teresa 17, Skopje.
      Norway: (DH Reikvam), A Maeland, J Bruun, Oslo University Hospital, Ullevaal.
      Poland: (B Knysz), B Szetela, M Inglot, Medical University, Wroclaw; E Bakowska, Centrum Diagnostyki i Terapii AIDS, Warsaw; R Flisiak, A Grzeszczuk, Medical University, Bialystok; M Parczewski, K Maciejewska, B Aksak-Was, Medical Univesity, Szczecin; M Beniowski, E Mularska, Osrodek Diagnostyki i Terapii AIDS, Chorzow; E Jablonowska, J Kamerys, K Wojcik, Wojewodzki Szpital Specjalistyczny, Lodz; I Mozer-Lisewska, B Rozplochowski,Poznan University of Medical Sciences, Poznan.
      Portugal: (A Zagalo), Hospital Santa Maria, Lisbon; K Mansinho, Hospital de Egas Moniz, Lisbon; F Maltez, Hospital Curry Cabral, Lisbon.
      Romania: (R Radoi), C Oprea, Carol Davila University of Medicine and Pharmacy Bucharest, Victor Babes Clinical Hospital for Infectious and Tropical Diseases, Bucharest.
      Russia: D Gusev, Medical Academy Botkin Hospital, St Petersburg; T Trofimova, Novgorod Centre for AIDS, Novgorod, I Khromova, Centre for HIV/AIDS & and Infectious Diseases, Kaliningrad; E Kuzovatova, Academician I.N.Blokhina Nizhny Novgorod Scientific Research Institute of Epidemiology and Microbiology, Nizhny Novgorod; E Borodulina, E Vdoushkina, Samara State Medical University, Samara.
      Serbia: (J Ranin), The Institute for Infectious and Tropical Diseases, Belgrade.
      Slovenia: (J Tomazic), University Clinical Centre Ljubljana, Ljubljana.
      Spain: (JM Miro), JM Miró, M. Laguno, E. Martinez, F. Garcia, JL Blanco, M. Martinez-Rebollar, J. Mallolas, P Callau, J Rojas, A Inciarta, Hospital Clinic – IDIBAPS University of Barcelona, Barcelona; S Moreno, S. del Campo, Hospital Ramon y Cajal, Madrid; B Clotet, A Jou, R Paredes, J Puig, JM Llibre, JR Santos, Infectious Diseases Unit & IrsiCaixa AIDS Research Institute, Hospital Germans Trias I Pujol, Badalona; P Domingo, M Gutierrez, G Mateo, MA Sambeat, Hospital Sant Pau, Barcelona; JM Laporte, Hospital Universitario de Alava, Vitoria-Gasteiz.
      Sweden: (P Novak), A Thalme, A Sönnerborg, Karolinska University Hospital, Stockholm; J Brännström, Venhälsan-Sodersjukhuset, Stockholm; L Flamholc, Malmö University Hospital, Malmö.
      Switzerland: (K Kusejko), D Braun, University Hospital Zurich; M Cavassini, University Hospital Lausanne; A Calmy, University Hospital Geneva; H Furrer, University Hospital Bern; M Battegay, University Hospital Basel; P Schmid, Cantonal Hospital St. Gallen.
      Ukraine: A Kuznetsova, Kharkov State Medical University, Kharkov; J Mikhalik, Crimean Republican AIDS centre, Simferopol; M Sluzhynska, Lviv Regional HIV/AIDS Prevention and Control CTR, Lviv.
      United Kingdom: A Milinkovic, St. Stephen's Clinic, Chelsea and Westminster Hospital, London; AM Johnson, S Edwards, Mortimer Market Centre, London; A Phillips, MA Johnson, A Mocroft, Royal Free and University College Medical School, London (Royal Free Campus); C Orkin, Royal London Hospital, London; A Winston, Imperial College School of Medicine at St. Mary's, London; A Clarke, Royal Sussex County Hospital, Brighton; C. Mackintosh, C Leen, Western General Hospital, Edinburgh.
      The following centers have previously contributed data to EuroSIDA:
      Medical University, Gdansk, Poland.
      Infectious Diseases Hospital, Sofia, Bulgaria.
      Hôpital de la Croix Rousse, Lyon, France.
      Hôpital de la Pitié-Salpétière, Paris, France.
      Unité INSERM, Bordeaux, France.
      Hôpital Edouard Herriot, Lyon, France.
      Bernhard Nocht Institut für Tropenmedizin, Hamburg, Germany.
      1st I.K.A Hospital of Athens, Athens, Greece.
      Ospedale Riuniti, Divisione Malattie Infettive, Bergamo, Italy.
      Ospedale di Bolzano, Divisione Malattie Infettive, Bolzano, Italy.
      Ospedale Cotugno,III Divisione Malattie Infettive, Napoli, Italy.
      Dérer Hospital, Bratislava, Slovakia.
      Hospital Carlos III, Departamento de Enfermedades Infecciosas, Madrid, Spain.
      Kiev Centre for AIDS, Kiev, Ukraine.
      Luhansk State Medical University, Luhansk, Ukraine.
      Odessa Region AIDS Center, Odessa, Ukraine.
      St Petersburg AIDS Centre, St Petersburg, Russia.
      Infectology Centre of Latvia, Riga, Latvia.
      University di Roma la Sapienza, Rome, Italy.
      Istituto Nazionale Malattie Infettive Lazzaro Spallanzani, Rome, Italy.
      EuroSIDA Steering Committee.
      Steering Committee: I Karpov, M Losso, J Lundgren, J Rockstroh, I Aho, LD Rasmussen, P Novak, G Wandeler, C Pradier, N Chkhartishvili, R Matulionyte, C Oprea, JD Kowalska, J Begovac, JM Miró, G Guaraldi, R Paredes.
      Chair: G Wandeler.
      Co-Chair: R Paredes.
      Study lead: L Peters.
      EuroSIDA staff.
      Coordinating Centre Staff: L Peters, JF Larsen, B Neesgaard, N Jaschinski, O Fursa, D Raben, D Kristensen, AH Fischer, SK Jensen, TW Elsing, M Gardizi.
      Statistical Staff: A Mocroft, A Phillips, J Reekie, A Cozzi-Lepri, A Pelchen-Matthews, A Roen, ES Tusch, W Bannister.
      ATHENA cohort.
      Amsterdam UMC, AMC site, Amsterdam: HIV treating physicians: M. van der Valk, S.E. Geerlings, A. Goorhuis, V.C. Harris, J.W. Hovius, B. Lempkes, F.J.B. Nellen, T. van der Poll, J.M. Prins, V. Spoorenberg, M. van Vugt, W.J. Wiersinga, F.W.M.N. Wit. HIV nurse consultants: C. Bruins, J. van Eden, I.J. Hylkema-van den Bout, A.M.H. van Hes, F.J.J. Pijnappel, S.Y. Smalhout, A.M. Weijsenfeld. HIV clinical virologists/chemists: N.K.T. Back, B. Berkhout, M.T.E. Cornelissen, R. van Houdt, M. Jonges, S. Jurriaans, C.J. Schinkel, K.C. Wolthers, H.L. Zaaijer. Amsterdam UMC, VUmc site, Amsterdam: HIV treating physicians: E.J.G. Peters, M.A. van Agtmael, R.S. Autar, M. Bomers, K.C.E. Sigaloff. HIV nurse consultants: M. Heitmuller, L.M. Laan. HIV clinical virologists/chemists: N.K.T. Back, B. Berkhout, M.T.E. Cornelissen, R. van Houdt, M. Jonges, S. Jurriaans, C.J. Schinkel, K.C. Wolthers, H.L. Zaaijer. Admiraal De Ruyter Ziekenhuis, Goes: HIV treating physicians: M. van den Berge, A. Stegeman. HIV nurse consultants: S. Baas, L. Hage de Looff. HIV clinical virologists/chemists: A. van Arkel, J. Stohr, B. Wintermans. Catharina Ziekenhuis, Eindhoven: HIV treating physicians: M.J.H. Pronk, H.S.M. Ammerlaan. HIV nurse consultants: E.S. de Munnik. HIV clinical virologists/chemists: B. Deiman, A.R. Jansz, V. Scharnhorst, J. Tjhie, M.C.A. Wegdam. DC Klinieken Lairesse – Hiv Focus Centrum, Amsterdam: HIV treating physicians: M. van der Valk, A. van Eeden, E. Hoornenborg, J. Nellen. HIV nurse consultants: W. Alers, L.J.M. Elsenburg, H. Nobel. HIV clinical virologists/chemists:C.J. Schinkel. ETZ (Elisabeth-TweeSteden Ziekenhuis), Tilburg: HIV treating physicians: M.E.E. van Kasteren, M.A.H. Berrevoets, A.E. Brouwer. HIV nurse specialist: B.A.F.M. de Kruijf-van de Wiel. HIV nurse consultants: A. Adams, M. Pawels-van Rijkevoorsel. HIV data collection: B.A.F.M. de Kruijf-van de Wiel. HIV clinical virologists/chemists: A.G.M. Buiting, J.L. Murck. Erasmus MC, Rotterdam: HIV treating physicians: C. Rokx, A.A. Anas, H.I. Bax, E.C.M. van Gorp, M. de Mendonça Melo, E. van Nood, J.L. Nouwen, B.J.A. Rijnders, C.A.M. Schurink, L. Slobbe, T.E.M.S. de Vries-Sluijs. HIV nurse consultants: N. Bassant, J.E.A. van Beek, M. Vriesde, L.M. van Zonneveld. HIV data collection: J. de Groot. HIV clinical virologists/chemists: J.J.A. van Kampen, M.P.G Koopmans, J.C. Rahamat-Langendoen. Flevoziekenhuis, Almere: HIV treating physicians: J. Branger, R.A. Douma. HIV nurse consultant: A.S. Cents-Bosma, C.J.H.M. Duijf-van de Ven. HagaZiekenhuis, Den Haag: HIV treating physicians: E.F. Schippers, C. van Nieuwkoop. HIV nurse consultants: J. Geilings, S. van Winden. HIV data collection: G. van der Hut. HIV clinical virologists/chemists: N.D. van Burgel. HMC (Haaglanden Medisch Centrum), Den Haag: HIV treating physicians: E.M.S. Leyten, L.B.S. Gelinck, F. Mollema. HIV nurse consultants: G.S. Wildenbeest. HIV clinical virologists/chemists: T. Nguyen. Isala, Zwolle: HIV treating physicians: P.H.P. Groeneveld, J.W. Bouwhuis, A.J.J. Lammers. HIV nurse consultants: A.G.W. van Hulzen, S. Kraan, M.S.M. Kruiper. HIV data collection: G.L. van der Bliek, P.C.J. Bor. HIV clinical virologists/chemists: S.B. Debast, G.H.J. Wagenvoort. Leids Universitair Medisch Centrum, Leiden: HIV treating physicians: A.H.E. Roukens, M.G.J. de Boer, H. Jolink, M.M.C. Lambregts, H. Scheper. HIV nurse consultants: W. Dorama, N. van Holten. HIV clinical virologists/chemists: E.C.J. Claas, E. Wessels. Maasstad Ziekenhuis, Rotterdam: HIV treating physicians: J.G. den Hollander, R. El Moussaoui, K. Pogany. HIV nurse consultants: C.J. Brouwer, D. Heida-Peters, E. Mulder, J.V. Smit, D. Struik-Kalkman. HIV data collection: T. van Niekerk. HIV clinical virologists/chemists: O. Pontesilli, C. van Tienen. Maastricht UMC+, Maastricht: HIV treating physicians: S.H. Lowe, A.M.L. Oude Lashof, D. Posthouwer, M.E. van Wolfswinkel. HIV nurse consultants: R.P. Ackens, K. Burgers, M. Elasri, J. Schippers. HIV clinical virologists/chemists: T.R.A. Havenith, M. van Loo. Medisch Centrum Leeuwarden, Leeuwarden: HIV treating physicians: M.G.A. van Vonderen, L.M. Kampschreur. HIV nurse consultants: M.C. van Broekhuizen, S, Faber. HIV clinical virologists/chemists: A. Al Moujahid. Medisch Spectrum Twente, Enschede: HIV treating physicians: G.J. Kootstra, C.E. Delsing. HIV nurse consultants: M. van der Burg-van de Plas, L. Scheiberlich. Noordwest Ziekenhuisgroep, Alkmaar: HIV treating physicians: W. Kortmann*, G. van Twillert*, R. Renckens, J. Wagenaar. HIV nurse consultants & HIV data collection: D. Ruiter-Pronk, F.A. van Truijen-Oud. HIV clinical virologists/chemists: J.W.T. Cohen Stuart, M. Hoogewerf, W. Rozemeijer, J.C. Sinnige. OLVG, Amsterdam: HIV treating physicians: K. Brinkman, G.E.L. van den Berk, K.D. Lettinga, M. de Regt, W.E.M. Schouten, J.E. Stalenhoef, J. Veenstra, S.M.E. Vrouenraets. HIV nurse consultants: H. Blaauw, G.F. Geerders, M.J. Kleene, M. Knapen, M. Kok, I.B. van der Meché, A.J.M. Toonen, S. Wijnands, E. Wttewaal. HIV clinical virologists: D. Kwa, T.J.W. van de Laar. Radboudumc, Nijmegen: HIV treating physicians: R. van Crevel, K. van Aerde, A.S.M. Dofferhoff, S.S.V. Henriet, H.J.M. ter Hofstede, J. Hoogerwerf, O. Richel. HIV nurse consultants: M. Albers, K.J.T. Grintjes-Huisman, M. de Haan, M. Marneef. HIV clinical virologists/chemists: M. McCall. HIV clinical pharmacology consultant: D. Burger. Rijnstate, Arnhem: HIV treating physicians: E.H. Gisolf, M. Claassen, R.J. Hassing,. HIV nurse consultants: G. ter Beest, P.H.M. van Bentum, M. Gelling, Y. Neijland. HIV clinical virologists/chemists: C.M.A. Swanink, M. Klein Velderman. Spaarne Gasthuis, Haarlem: HIV treating physicians: S.F.L. van Lelyveld, R. Soetekouw. HIV nurse consultants: L.M.M. van der Prijt, J. van der Swaluw. HIV clinical virologists/chemists: J.S. Kalpoe, A. Wagemakers, A. Vahidnia. Medisch Centrum Jan van Goyen, Amsterdam: HIV treating physicians: F.N. Lauw, D.W.M. Verhagen. HIV nurse consultants: M. van Wijk. Universitair Medisch Centrum Groningen, Groningen: HIV treating physicians: W.F.W. Bierman, M. Bakker, R.A. van Bentum, M.A. van den Boomgaard, J. Kleinnijenhuis, E. Kloeze, A. Middel, D.F. Postma, H.M. Schenk, Y. Stienstra, M. Wouthuyzen-Bakker. HIV nurse consultants: A. Boonstra, H. de Jonge, M.M.M. Maerman, D.A. de Weerd. HIV clinical virologists/chemists: K.J. van Eije, M. Knoester, C.C. van Leer-Buter, H.G.M. Niesters. Universitair Medisch Centrum, Utrecht: HIV treating physicians: T.Mudrikova, R.E. Barth, A.H.W. Bruns, P.M. Ellerbroek, M.P.M. Hensgens, J.J. Oosterheert, E.M. Schadd, A. Verbon, B.J. van Welzen. HIV nurse consultants: H. Berends, B.M.G. Griffioen-van Santen, I. de Kroon. HIV clinical virologists/chemists: F.M. Verduyn Lunel, A.M.J. Wensing.
      Coordinating center Board of directors: M. van der Valk, S. Zaheri. HIV data analysis: A.C. Boyd, D.O. Bezemer, A.I. van Sighem, C. Smit, F.W.M.N. Wit. Data HIV data management and quality control: M.M.J. Hillebregt, T.J. Woudstra, T. Rutkens. HIV data monitoring: D. Bergsma, N.M. Brétin, K.J. Lelivelt, L. van de Sande, K.M. Visser. S.T. van der Vliet. HIV data collection: F. Paling, L.G.M. de Groot-Berndsen, M. van den Akker, R. Alexander, Y. Bakker, A. El Berkaoui, M. Bezemer-Goedhart, E.A. Djoechro, M. Groters, L.E. Koster, C.R.E. Lodewijk, E.G.A. Lucas, L. Munjishvili, B.M. Peeck, C.M.J. Ree, R. Regtop, A.F. van Rijk, Y.M.C. Ruijs-Tiggelman, P.P. Schnörr, M.J.C. Schoorl, E.M Tuijn, D.P. Veenenberg, E.C.M Witte. Patiënt registration: D. Bergsma, N.M. Brétin, Y.M.C. Ruijs-Tiggelman.
      ANRS CO3 AQUITAINE - AquiVIH-NA.
      Cohort scientific committee: P. Bellecave, P. Blanco, F. Bonnet (Chair), S. Bouchet, D. Breilh, C. Cazanave, S. Desjardin, V. Gaborieau, A. Gimbert, M. Hessamfar, L. Lacaze-Buzy, D. Lacoste, ME Lafon, E. Lazaro, O. Leleux., F. Le Marec, G. Le Moal, D. Malvy, L. Marchand, P. Mercié, D. Neau, I. Pellegrin, A. Perrier, V. Petrov-Sanchez, M.O. Vareil, L. Wittkop (Methodologist).
      Participating centers: Hôpital Saint André, CHU de Bordeaux, Médecine Interne et Maladies Infectieuses, (N. Bernard, F. Bonnet, D. Bronnimann H. Chaussade, D. Dondia, P. Duffau, I. Faure, M. Hessamfar, P Mercié, P. Morlat, E. Mériglier, F. Paccalin, E. Riebero, C. Rivoisy, MA Vandenhende); Hôpital Pellegrin, CHU de Bordeaux, Maladies Infectieuses et Tropicales, (L. Barthod, C. Cazanave, FA. Dauchy, A. Desclaux, M. Ducours, H. Dutronc, A. Duvignaud, J. Leitao, M. Lescure, D. Neau, D. Nguyen, D. Malvy, T. Pistone, M. Puges, G. Wirth); Hôpital Haut-Lévêque, CHU de Bordeaux, Médecine Interne et Maladies Infectieuses, (C. Courtault, F. Camou, C. Greib, E. Lazaro, JL. Pellegrin, E. Rivière, JF. Viallard); Hôpital d’Agen, Médecine Interne (Y. Imbert, M. Thierry-Mieg, P. Rispal); Hôpital de Libourne, Médecine Interne (O. Caubet, H. Ferrand, S. Tchamgoué); Hôpital de Bayonne, Maladies Infectieuses (S. Farbos, MO. Vareil, H. Wille); Hôpital de Dax, Médecine Interne et Maladies Infectieuses, (K. Andre, L. Caunegre, Y. Gerard, F. Osorio-Perez); Hôpital Saint-Cyr/Villeneuve-sur-Lot, Maladies Infectieuses, (I. Chossat); Hôpital de Mont de Marsan, Médecine Interne et Maladies Infectieuses, (G. Iles, Y. Gerard, M. Labasse-Depis, F. Lacassin); Hôpital d’Arcachon, Médecine Interne, (A. Barret, C. Courtault); Hôpital de Périgueux, Médecine Interne et Maladies Infectieuses, (B Castan, J. Koffi, N. Rouanes, A. Saunier, JB Zabbe); Hôpital de Pau, Médecine Interne et Maladies Infectieuses, (G. Dumondin, V. Gaborieau); Hôpital d’Orthez, Médecine Interne, (Y. Gerard); CHU de Poitiers, Médecine Interne et Maladies Infectieuses, (G. Beraud, G. Le Moal, M. Catroux, M. Garcia, V. Giraud, JP. Martellosio, F. Roblot); Hôpital de Saintes, Médecine Interne, (T. Pasdeloup); Hôpital d’Angoulême, Médecine Interne, (A. Riché, M. Grosset, S. Males, C. Ngo Bell); Hôpital de Jonzac, Maladies Infectieuses, (T. Pasdeloup), Hôpital de Saint jean d’Angely, Maladies Infectieuses, (T. Pasdeloup). Other departments: Immunology: P. Blanco, I. Pellegrin; CRB-BBS: C. Carpentier, I. Pellegrin; Virology: P. Bellecave, ME. Lafon, C. Tumiotto; Pharmacology: S. Bouchet, D. Breilh, G. Miremeont-Salamé; Data collection: D. Arma, G. Arnou, MJ Blaizeau, P. Camps, M. Decoin, S. Delveaux, F. Diarra, L. Gabrea, S. Lawson-Ayayi, E. Lenaud, D. Plainchamps, A. Pougetoux, B. Uwamaliya, K. Zara; IT departement: V. Conte, M. Gapillout; Project Team: O. Leleux (Project Leader), F. Le Marec (Statistitien), A. Perrier (Data Manager).

      Appendix A. Supplementary data

      The following is the supplementary data to this article:

      References

      Author names in bold designate shared co-first authorship.
        • Perz J.F.
        • Armstrong G.L.
        • Farrington L.A.
        • Hutin Y.J.F.
        • Bell B.P.
        The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide.
        J Hepatol. 2006; 45: 529-538https://doi.org/10.1016/j.jhep.2006.05.013
        • Kanwal F.
        • Singal A.G.
        Surveillance for Hepatocellular Carcinoma: Current Best Practice and Future Direction.
        Gastroenterology. 2019; 157: 54-64https://doi.org/10.1053/j.gastro.2019.02.049
        • Costentin C.E.
        • Layese R.
        • Bourcier V.
        • Cagnot C.
        • Marcellin P.
        • Guyader D.
        • et al.
        Compliance With Hepatocellular Carcinoma Surveillance Guidelines Associated With Increased Lead-Time Adjusted Survival of Patients With Compensated Viral Cirrhosis: A Multi-Center Cohort Study.
        Gastroenterology. 2018; 155 (e10): 431-442https://doi.org/10.1053/j.gastro.2018.04.027
        • Willemse S.
        • Smit C.
        • Sogni P.
        • Sarcletti M.
        • Uberti-Foppa C.
        • Wittkop L.
        • et al.
        Low compliance with hepatocellular carcinoma screening guidelines in hepatitis B/C virus co-infected HIV patients with cirrhosis.
        J Viral Hepat. 2019; 26: 1224-1228https://doi.org/10.1111/jvh.13146
        • Patel N.
        • Post F.A.
        Surveillance for hepatocellular carcinoma in people of African ancestry with HIV and Hepatitis B.
        Int J STD AIDS. 2022; 33: 202-204https://doi.org/10.1177/09564624211042828
        • Wandeler G.
        • Mauron E.
        • Atkinson A.
        • Dufour J.-F.
        • Kraus D.
        • Reiss P.
        • et al.
        Incidence of hepatocellular carcinoma in HIV/HBV-coinfected patients on tenofovir therapy: Relevance for screening strategies.
        J Hepatol. 2019; 71: 274-280https://doi.org/10.1016/j.jhep.2019.03.032
        • Papatheodoridis G.
        • Dalekos G.
        • Sypsa V.
        • Yurdaydin C.
        • Buti M.
        • Goulis J.
        • et al.
        PAGE-B predicts the risk of developing hepatocellular carcinoma in Caucasians with chronic hepatitis B on 5-year antiviral therapy.
        J Hepatol. 2016; 64: 800-806https://doi.org/10.1016/j.jhep.2015.11.035
        • European Association for the Study of the Liver (EASL)
        Clinical Practice Guidelines on the management of hepatitis B virus infection.
        J Hepatol. 2017; 67: 370-398https://doi.org/10.1016/j.jhep.2017.03.021
      1. European AIDS Clinical Society (EACS). Guidelines for the management of people living with HIV 2021. https://www.eacsociety.org/media/final2021eacsguidelinesv11.0_oct2021.pdf (accessed February 25, 2022).

        • Scherrer A.U.
        • Traytel A.
        • Braun D.L.
        • Calmy A.
        • Battegay M.
        • Cavassini M.
        • et al.
        Cohort Profile Update: The Swiss HIV Cohort Study (SHCS).
        Int J Epidemiol. 2022; 51 (33–34j)https://doi.org/10.1093/ije/dyab141
        • Boender T.S.
        • Smit C.
        • van Sighem A.
        • Bezemer D.
        • Ester C.J.
        • Zaheri S.
        • et al.
        AIDS Therapy Evaluation in the Netherlands (ATHENA) national observational HIV cohort: cohort profile.
        BMJ Open. 2018; 8e022516https://doi.org/10.1136/bmjopen-2018-022516
        • Collin A.
        • Le Marec F.
        • Vandenhende M.-A.
        • Lazaro E.
        • Duffau P.
        • Cazanave C.
        • et al.
        Incidence and Risk Factors for Severe Bacterial Infections in People Living with HIV. ANRS CO3 Aquitaine Cohort, 2000-2012.
        PLoS One. 2016; 11e0152970https://doi.org/10.1371/journal.pone.0152970
        • Laut K.
        • Kirk O.
        • Rockstroh J.
        • Phillips A.
        • Ledergerber B.
        • Gatell J.
        • et al.
        The EuroSIDA study: 25 years of scientific achievements.
        HIV Med. 2020; 21: 71-83https://doi.org/10.1111/hiv.12810
        • Collins G.S.
        • Reitsma J.B.
        • Altman D.G.
        • Moons K.G.M.
        Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD): the TRIPOD statement.
        Ann Intern Med. 2015; 162: 55-63https://doi.org/10.7326/M14-0697
        • Royston P.
        • Altman D.G.
        External validation of a Cox prognostic model: principles and methods.
        BMC Med Res Methodol. 2013; 13: 33https://doi.org/10.1186/1471-2288-13-33
        • Heimbach J.K.
        • Kulik L.M.
        • Finn R.S.
        • Sirlin C.B.
        • Abecassis M.M.
        • Roberts L.R.
        • et al.
        AASLD guidelines for the treatment of hepatocellular carcinoma.
        Hepatology. 2018; 67: 358-380https://doi.org/10.1002/hep.29086
        • Blanche P.
        • Dartigues J.-F.
        • Jacqmin-Gadda H.
        Estimating and comparing time-dependent areas under receiver operating characteristic curves for censored event times with competing risks.
        Stat Med. 2013; 32: 5381-5397https://doi.org/10.1002/sim.5958
        • van Buuren S.
        • Groothuis-Oudshoorn K.
        mice: Multivariate Imputation by Chained Equations in R.
        J Stat Softw. 2011; 45: 1-67https://doi.org/10.18637/jss.v045.i03
      2. Rubin DB. Multiple Imputation for Nonresponse in Surveys. Wiley; 1987. https://doi.org/10.1002/9780470316696.

        • Marshall A.
        • Altman D.G.
        • Holder R.L.
        • Royston P.
        Combining estimates of interest in prognostic modelling studies after multiple imputation: current practice and guidelines.
        BMC Med Res Methodol. 2009; 9: 57https://doi.org/10.1186/1471-2288-9-57
      3. R Core Team. R: A Language and Environment for Statistical Computing 2022. https://www.R-project.org/(accessed April 4, 2022).

        • Wickham H.
        • Averick M.
        • Bryan J.
        • Chang W.
        • McGowan L.
        • François R.
        • et al.
        Welcome to the tidyverse.
        J Open Source Softw. 2019; 4: 1686https://doi.org/10.21105/joss.01686
        • Yang J.D.
        • Gyedu A.
        • Afihene M.Y.
        • Duduyemi B.M.
        • Micah E.
        • Kingham T.P.
        • et al.
        Hepatocellular Carcinoma Occurs at an Earlier Age in Africans, Particularly in Association With Chronic Hepatitis B.
        Am J Gastroenterol. 2015; 110: 1629-1631https://doi.org/10.1038/ajg.2015.289
        • European Association for the Study of the Liver
        EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma.
        J Hepatol. 2018; 69: 182-236https://doi.org/10.1016/j.jhep.2018.03.019
        • Brouwer W.P.
        • van der Meer A.J.P.
        • Boonstra A.
        • Plompen E.P.C.
        • Pas S.D.
        • de Knegt R.J.
        • et al.
        Prediction of long-term clinical outcome in a diverse chronic hepatitis B population: Role of the PAGE-B score.
        J Viral Hepat. 2017; 24: 1023-1031https://doi.org/10.1111/jvh.12727
        • Kim M.N.
        • Hwang S.G.
        • Rim K.S.
        • Kim B.K.
        • Park J.Y.
        • Kim D.Y.
        • et al.
        Validation of PAGE-B model in Asian chronic hepatitis B patients receiving entecavir or tenofovir.
        Liver Int. 2017; 37: 1788-1795https://doi.org/10.1111/liv.13450
        • Yip T.C.-F.
        • Wong G.L.-H.
        • Wong V.W.-S.
        • Tse Y.-K.
        • Liang L.Y.
        • Hui V.W.-K.
        • et al.
        Reassessing the accuracy of PAGE-B-related scores to predict hepatocellular carcinoma development in patients with chronic hepatitis B.
        J Hepatol. 2020; 72: 847-854https://doi.org/10.1016/j.jhep.2019.12.005
        • Kim H.N.
        • Newcomb C.W.
        • Carbonari D.M.
        • Roy J.A.
        • Torgersen J.
        • Althoff K.N.
        • et al.
        Risk of HCC With Hepatitis B Viremia Among HIV/HBV-Coinfected Persons in North America.
        Hepatology. 2021; 74: 1190-1202https://doi.org/10.1002/hep.31839
        • Yang J.D.
        • Altekruse S.F.
        • Nguyen M.H.
        • Gores G.J.
        • Roberts L.R.
        Impact of country of birth on age at the time of diagnosis of hepatocellular carcinoma in the United States.
        Cancer. 2017; 123: 81-89https://doi.org/10.1002/cncr.30246
        • Yang J.D.
        • Mohamed E.A.
        • Aziz A.O.A.
        • Shousha H.I.
        • Hashem M.B.
        • Nabeel M.M.
        • et al.
        Characteristics, management, and outcomes of patients with hepatocellular carcinoma in Africa: a multicountry observational study from the Africa Liver Cancer Consortium.
        Lancet Gastroenterol Hepatol. 2017; 2: 103-111https://doi.org/10.1016/S2468-1253(16)30161-3
        • Collins G.S.
        • Ogundimu E.O.
        • Altman D.G.
        Sample size considerations for the external validation of a multivariable prognostic model: a resampling study.
        Stat Med. 2016; 35: 214-226https://doi.org/10.1002/sim.6787
        • Béguelin C.
        • Moradpour D.
        • Sahli R.
        • Suter-Riniker F.
        • Lüthi A.
        • Cavassini M.
        • et al.
        Hepatitis delta-associated mortality in HIV/HBV-coinfected patients.
        J Hepatol. 2017; 66: 297-303https://doi.org/10.1016/j.jhep.2016.10.007