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

Bernard Surial, Adria Ramirez Mena, Marie Roumet, Andreas Limacher, Colette Smit, Olivier Leleux, Amanda Mocroft, Marc van der Valk, Fabrice Bonnet, Lars Peters, et al.

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## To cite this version:

Bernard Surial, Adria Ramirez Mena, Marie Roumet, Andreas Limacher, Colette Smit, et al. External validation of the PAGE-B score for HCC risk prediction in people living with HIV/HBV coinfection. Journal of Hepatology, 2023, 78 (5), pp.947-957. 10.1016/j.jhep.2022.12.029. hal-04001881

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Journal Pre-proof

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

Bernard Surial, Adrià Ramírez Mena, Marie Roumet, Andreas Limacher, Colette Smit, Olivier Leleux, Amanda Mocroft, Marc van der Valk, Fabrice Bonnet, Lars Peters, Jürgen K. Rockstroh, Huldrych F. Günthard, Annalisa Berzigotti, Andri Rauch, Gilles Wandeler, the Swiss HIV Cohort Study, ATHENA Observational Cohort Study, EuroSIDA, ANRS CO3 Aquitaine Cohort

PII: S0168-8278(23)00011-9

DOI: https://doi.org/10.1016/j.jhep.2022.12.029

Reference: JHEPAT 9006

To appear in: *Journal of Hepatology*

Received Date: 6 October 2022

Revised Date: 21 December 2022

Accepted Date: 23 December 2022

Please cite this article as: Surial B, Mena AR, Roumet M, Limacher A, Smit C, Leleux O, Mocroft A, van der Valk M, Bonnet F, Peters L, Rockstroh JK, Günthard HF, Berzigotti A, Rauch A, Wandeler G, the Swiss HIV Cohort Study, ATHENA Observational Cohort Study, EuroSIDA, ANRS CO3 Aquitaine Cohort, External validation of the PAGE-B score for HCC risk prediction in people living with HIV/HBV coinfection, *Journal of Hepatology* (2023), doi: https://doi.org/10.1016/j.jhep.2022.12.029.

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© 2023 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.

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HIV

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Hepatitis B

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PAGE-B

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Age

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Gender

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Platelets

PAGE-B below 10

99.4%
will not
develop HCC

PAGE-B 10 or higher

<figure><img src="image_9.png" /></figure>

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

3 Bernard Surial¹, Adrià Ramírez Mena¹,², Marie Roumet³, Andreas Limacher³, Colette Smit⁴, Olivier

4 Leleux⁵, Amanda Mocroft⁶,⁷, Marc van der Valk⁴,⁸, Fabrice Bonnet⁵,⁹, Lars Peters⁶, Jürgen K.

5 Rockstroh¹⁰, Huldrych F. Günthard¹¹,¹², Annalisa Berzigotti¹³, Andri Rauch¹*, Gilles Wandeler¹*, and
6 the Swiss HIV Cohort Study, ATHENA Observational Cohort Study, EuroSIDA, ANRS CO3 Aquitaine

7 Cohort

8

9 **Affiliations**

10 ¹Department of Infectious Diseases, Inselspital, Bern University Hospital, Bern, Switzerland

11 ²Graduate School of Health Sciences, University of Bern, Bern, Switzerland

12 ³CTU Bern, University of Bern, Bern, Switzerland

13 ⁴Stichting hiv monitoring, Amsterdam, the Netherlands

14 ⁵University of Bordeaux, INSERM, Institut Bergonié, BPH, U1219, CIC-EC 1401, F-33000, Bordeaux,
15 France

16 ⁶CHIP, Rigshospitalet, Copenhagen, Denmark

17 ⁷Centre for Clinical Research Epidemiology, Modelling and Evaluation (CREME), Institute for Global
18 Health, University College London, London, UK

19 ⁸Department of Infectious Diseases, Amsterdam Infection and Immunity Institute (AI&II), Amsterdam
20 UMC, University of Amsterdam, Amsterdam, the Netherlands

21 ⁹CHU Bordeaux, Hôpital Saint-André, Service de médecine interne et maladies infectieuses,
22 Bordeaux, France

23 ¹⁰Department of Medicine I, University Hospital Bonn, Bonn, Germany

24 ¹¹Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich,
25 Switzerland

26 ¹²Institute of Medical Virology, University of Zurich, Zurich, Switzerland

27 ¹³Hepatology, Department for Visceral Surgery and Medicine, Bern University Hospital, Bern,
28 Switzerland

29 *Authors contributed equally

30
31 **Corresponding author:**
32 Bernard Surial M.D., Department of Infectious Diseases, Inselspital, Bern University Hospital, Bern,
33 Switzerland; phone: +41 31 632 27 45; email: bernard.sorial@insel.ch

34

35 **Alternate corresponding author:**
36 Gilles Wandeler M.D. MSc, Department of Infectious Diseases, Inselspital, Bern University Hospital,
37 Bern, Switzerland; phone: +41 31 632 27 45; email: gilles.wandeler@insel.ch

38

39 **Abstract:** 275 words; **Text:** 5'799 words (abstract, references, tables, legends); **Figures/Tables:** 5.

40

41 **Keywords:** Hepatitis B virus; HIV infection; hepatocellular carcinoma; liver cirrhosis; liver neoplasms;
42 risk assessment; risk prediction models; model validation; tenofovir.

43

44 **Potential conflicts of interest:** BS reports support to his institution for advisory boards and travel
45 grants from Gilead Sciences and ViiV, outside of the present work. AM has received honoraria, travel
46 support, lecture fees and/or consultancy fees from ViiV, Gilead and Eiland and Bonnin. MvdV reports
47 support to his institution for advisory boards and unrestricted research grants from Gilead Sciences,
48 Merck and ViiV. FB has received travel grants and honoraria from ViiV Healthcare, Gilead, ViiV,
49 Janssen, and MSD, and support for attending meetings from Gilead, Janssen, MSD, and ViiV
50 Healthcare. JKR reports honoraria for himself for advisory boards or DSMB participation and speaking
51 at educational events from Abivax, Galapagos, Gilead Sciences, Janssen, Merck, Theratechnologies
52 and ViiV, outside of the submitted work. HFG has received unrestricted research grants from Gilead
53 Sciences; fees for data and safety monitoring board membership from Merck; consulting/advisory
54 board membership fees from Gilead Sciences, Merck, Johnson and Johnson, Novartis and ViiV
55 Healthcare; and grants from the Swiss National Science Foundation, the Yvonne Jacob Foundation
56 and from National Institutes of Health. AR reports support to his institution for advisory boards and/or
57 travel grants from MSD, Gilead Sciences, Pfizer and Abbvie, and an investigator-initiated trial (IIT)
58 grant from Gilead Sciences. All remuneration went to his home institution and not to AR personally,
59 and all remuneration was provided outside the submitted work. GW reports unrestricted research
60 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.

63

**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-providers and http://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.

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**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.

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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.

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95 **ABSTRACT**

96 **Background & Aims**

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

101 **Methods**

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

108 **Results**

109 In total, 2'963 individuals with HIV/HBV coinfection on tenofovir-containing ART were included. PAGE-
110 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
111 years, HCC occurred in 68 individuals (2.58/1000 patient-years, 95% confidence interval [CI] 2.03-
112 3.27). The regression slope of the prognostic index for developing HCC within 15 years was 0.93 (95%
113 CI 0.61-1.25), and the pooled c-index was 0.77 (range 0.73-0.80), both indicating good model
114 discrimination. Cumulative incidence of HCC was lower in our study compared to the derivation study.
115 A PAGE-B cut-off of <10 had a negative predictive value for developing HCC within 5 years of 99.4%.
116 Restricting efforts to individuals with a PAGE-B of ≥10 would spare HCC screening in 27% of
117 individuals.
118 **Conclusions**

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

121 **IMPACT AND IMPLICATIONS**

122 Chronic hepatitis B virus (HBV) infection is the most important cause of hepatocellular carcinoma (HCC)
123 among people living with HIV, and valid risk prediction may guide HCC screening efforts to high-risk
124 individuals. We aimed at validating PAGE-B, a risk prediction tool that is based on age, gender, and
125 platelets, among 2963 individuals with HIV/HBV coinfection who received tenofovir-containing
126 antiretroviral therapy. In the present study, PAGE-B showed good discrimination, adequate calibration,
127 and a cut-off of less than 10 had a negative predictive value for developing HCC within 5 years of
128 99.4%. These results indicate that PAGE-B is a simple and valid risk prediction tool to determine the
129 need for HCC screening among people living with HIV and HBV.

130
131 INTRODUCTION

132 Between 5 and 15% of people living with HIV (PLWH) also have a chronic hepatitis B virus (HBV) 133 infection, the single most important cause of end-stage liver disease and hepatocellular carcinoma 134 (HCC) worldwide [1]. Screening individuals with HBV infection and a high risk for HCC using ultrasound 135 every 6 months is recommended to detect cancers at an early and curable stage [2,3]. However, 136 screening uptake remains suboptimal, and therefore represents a missed opportunity to prevent HCC- 137 related deaths [4,5]. We previously showed that among individuals with HIV and HBV, those who were 138 older than 46 years or had liver cirrhosis had the highest risk of developing HCC [6]. To guide clinicians 139 in deciding whether a patient needs HCC screening or not, simple HCC risk prediction tools could help 140 with risk stratification.

141 PAGE-B, a prognostic score including age, sex and platelet count at initiation of antiviral therapy, was 142 derived from a multi-country study of 1'815 European individuals with HBV mono-infection, and reliably 143 predicted their 5-year HCC risk [7]. As the score is based on inexpensive and readily available 144 measurements that do not include the evaluation of cirrhosis, PAGE-B has become an established tool 145 for clinicians to discuss HCC screening with patients, including in settings with limited access to liver 146 biopsy or transient elastography (TE) [8]. The use of PAGE-B is also suggested by the European AIDS 147 Clinical Society guidelines to assess the HCC risk in individuals with HIV/HBV coinfection [9], despite 148 the lack of evaluation of its predictive value in this population. The validity of this score in PLWH is 149 challenged by differences in HCC incidence, the presence of HIV-induced thrombocytopenia and the 150 high prevalence of additional HCC risk factors such as hepatitis C virus (HCV) and hepatitis delta virus 151 (HDV) infections, as well as alcohol use [6].

152 To provide scientific evidence for HCC surveillance recommendations, we conducted an external 153 validation of the prognostic performance of the PAGE-B score in persons living with HIV and HBV from 154 a large cohort collaboration in Europe.

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# PATIENTS AND METHODS

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## Study setting and participants

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We considered participants with HBV from four prospective longitudinal cohorts: the Swiss HIV Cohort Study (SHCS) [10], the AIDS Therapy Evaluation in the Netherlands (ATHENA) Cohort [11], the Agence Nationale de Recherches sur le Sida (ANRS) CO3 Aquitaine Cohort-AQUIVIH-NA (Aquitaine) [12], and EuroSIDA [13]. 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 [14].

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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 [7] 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.

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## Outcomes and definitions

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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

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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.

189 Statistical Analyses

190 Cumulative incidence of HCC stratified by the same PAGE-B categories as in the original derivation 191 study (<10, 10-17, ≥18) was presented using Kaplan Meier curves [7]. The predictive performance of 192 the PAGE-B score during follow-up was assessed using discrimination and calibration, as 193 recommended by Royston and Altman [15]. Observation time was right-censored at 15 years to limit 194 the excess influence of individuals with longer follow-up. To assess model discrimination, we first 195 calculated the prognostic index using the linear predictor based on the regression coefficients of the 196 PAGE-B model (Figure S1). We then fitted a Cox regression model with the prognostic index as a 197 covariate, where a slope <1 indicates poorer discrimination compared to the original study, and >1 198 indicates better discrimination. We further measured discrimination using Harrell's c-index, which gives 199 the proportion of patients where predictions and outcomes are concordant, and is equivalent to the area 200 under the receiver operating curve. Calibration was assessed by comparing cumulative incidence 201 estimates, calculated using the Kaplan-Meier method, between the present validation and the original 202 validation study. Screening for HCC is considered effective if the yearly risk is above 0.2% (equal to 3% 203 in 15 years assuming a stable risk per year) [16]. To calculate the PAGE-B cut-off that reflects a risk 204 above that threshold, we calculated cumulative incidence of HCC within 15 years using the Kaplan- 205 Meier method. Sensitivity, specificity, negative and positive predictive values at 5 years (as in the 206 original derivation study) were calculated from a time-dependent ROC curve analysis using the 207 timeROC package [17].

208 As information on platelets at tenofovir start was missing in 36% of patients, model validation was 209 performed after multiple imputation of predictors. Assuming missingness at random, we performed 210 multivariable imputation by chained equations using the mice package [18]. The variables used for the 211 multiple imputation model were the outcome (HCC) and 19 covariates (Table S2). The distribution of 212 imputed platelet values is shown in Figure S2. After imputing 50 datasets, all calculations were
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performed individually on each dataset, and estimates were combined using Rubin's rules [19] or by
providing the median and the range of values (c-index) [20]. All analyses were performed using R,
version 4.1.3 [21,22].

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Sensitivity Analyses

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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 [23]. 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.

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# RESULTS

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## Study population

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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 (Figure 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 [7], 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).

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## Occurrence of HCC

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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).

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255 PAGE-B model validation

256 For 1'890 individuals (63.8%), a PAGE-B score at the time of tenofovir start could be calculated based
257 on complete case data. The distributions of PAGE-B values were similar in the complete case and
258 imputation datasets (Figure 1A and 1C). In the complete case dataset, the PAGE-B score was <10 in
259 522 (27.6%), between 10 and 17 in 1'068 (56.5%), and ≥18 in 300 individuals (15.9%). After multiple
260 imputation, 785 individuals (26.5%) had a score <10, 1711 (57.7%) had a score between 10 and 17,
261 and 466 (15.7%) had a score ≥18. Thirty-nine HCC cases (55.7%) occurred in individuals with a PAGE-
262 B of 18 or higher, 27 (38.6%) occurred in individuals with a PAGE-B between 10 and 17, whereas only
263 4 (5.7%) individuals with a PAGE-B score <10 developed an HCC (Figure 1B and 1D). Of 4 individuals
264 with an HCC and a PAGE-B score <10, the median age was 37 years, 3 were of African and one was
265 of Asian origin, one individual had evidence of liver cirrhosis on TE, and another individual had
266 coinfection with HDV.

267 The regression slope of the prognostic index for the development of HCC within 15 years after tenofovir
268 start was 0.93 (95% CI 0.61 to 1.25). This value was close to 1.0 (p-value = 0.67) and indicated
269 preserved discrimination compared to the derivation study. Similarly, PAGE-B showed good
270 discrimination with a pooled c-index of 0.77 (range 0.73 to 0.80), which was close to the results after
271 internal (c-index: 0.81) and external (c-index: 0.82) validation performed in the original PAGE-B
272 derivation study [7]. Visual inspection of the Kaplan-Meier curves showed that the highest cumulative
273 incidence of HCC was in individuals with a PAGE-B ≥18, followed by those with a PAGE-B between 10
274 and 17, whereas the lowest incidence was seen in individuals with a PAGE-B <10 (Figure 2A). Model
275 calibration was assessed by comparing the cumulative incidence of HCC from our study with the results
276 of the derivation study. The cumulative incidence of HCC over five years was 5.6% in individuals with
277 a PAGE-B score ≥18 in our study compared to 17% in the derivation study. We also found a lower
278 cumulative incidence in individuals with a PAGE-B score between 10 and 17 compared to the derivation
279 study and this difference was observed throughout the full follow-up time (Table 2).

280 Of 2438 non-African participants, 61 developed HCC: 37 (60.7%) had a PAGE-B ≥18, 23 (37.7%) had
281 a PAGE-B between 10 and 17, and only one individual (1.6%) had a PAGE-B <10. HCC incidence rates
282 between individuals of African (2.03 per 1'000 patient-years, 95% CI 1.06 to 3.90) and of non-African
283 origin (2.69 per 1'000 patient-years, 95% CI 2.08 - 3.47) did not differ significantly (p = 0.43). The
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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).

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## Sensitivity analyses

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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).

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## Screening cut-off

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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 [7], 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%, Figure 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%.

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309 DISCUSSION

310 In this external validation study, the PAGE-B score showed good accuracy in predicting the HCC risk
311 in a large collaboration of European cohorts of individuals living with HIV and HBV infection. Similar to
312 the original derivation study [7], individuals with a score below 10 were at very low risk of HCC, with a
313 negative predictive value above 99%, confirming the usefulness of PAGE-B to target HCC surveillance
314 efforts in individuals with HIV/HBV coinfection. In the subset of participants with a low PAGE-B score,
315 3 of 4 HCC cases occurred in individuals of African origin.

316 Current guidelines suggest that individuals with HBV monoinfection and a PAGE-B score <10 do not
317 need HCC screening because of a very low risk of HCC [24]. In the original derivation study, a score of
318 <10 had a negative predictive value of 100%, meaning that no patient experienced HCC below that cut-
319 off [7]. We found a slightly lower negative predictive value of 99.4% in the full study population, and
320 99.8% after excluding individuals of African origin. These estimates are in line with the findings of
321 previous PAGE-B external validation studies in individuals with HBV mono-infection [25,26]. Although
322 the risk for HCC with a score <10 was not 0% in our study, the yearly risk for HCC was below the
323 recommended threshold of 0.2%, and therefore it seems justified to apply the same cut-offs to
324 individuals with and without HIV coinfection. Since 27% of individuals in our study had a PAGE-B <10,
325 targeting screening efforts to individuals with a PAGE-B of 10 and higher would substantially reduce
326 the need for HCC surveillance. Based on our results, even a higher threshold of <12 could be
327 considered, as the yearly HCC risk remained below 0.2% in those individuals, which would spare HCC
328 screening in 473 (16%) additional individuals. However, the potential benefits of using a higher PAGE-
329 B score cut-off than in the original derivation study need to be confirmed in other cohorts of individuals
330 with HIV/HBV coinfection.

331 In our study, PAGE-B model discrimination was similar to the original derivation study [7] and
332 comparable to other external validation studies performed among individuals with HBV monoinfection
333 in Europe and Asia [25,27]. Our incidence of HCC was comparable to other cohorts of Caucasian
334 participants with HIV/HBV coinfection [28], but markedly lower than in the original derivation study
335 across all PAGE-B categories, leading to differences in model calibration. These discrepancies were
336 most likely driven by differences in how HBV infection was defined across studies: To be included in
337 the derivation study, individuals needed to have confirmed HBsAg positivity for at least 6 months,
338 increased transaminases, and an HBV-DNA above 2000 IU/mL, in line with current HBV treatment
guidelines [7,8]. 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 [9]. 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 [26]. 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 [26]. 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 [23,29,30], 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 [9]. 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 [31]. 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 [32], 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.
378 ACKNOWLEDGMENTS

379 The authors thank all patients, physicians and nurses associated with the participating cohorts.

380

381 Members of the Swiss HIV Cohort Study (SHCS)

382 Abela I, Aebi-Popp K, Anagnostopoulos A, Battegay M, Bernasconi E, Braun DL, Bucher HC, Calmy
383 A, Cavassini M, Ciuffi A, Dollenmaier G, Egger M, Elzi L, Fehr J, Fellay J, Furrer H, Fux CA, Günthard
384 HF (President of the SHCS), Hachfeld A, Haerry D (deputy of "Positive Council"), Hasse B, Hirsch
385 HH, Hoffmann M, Hösli I, Huber M, Jackson-Perry D (patient representatives), Kahlert CR (Chairman
386 of the Mother & Child Substudy), Kaiser L, Keiser O, Klimkait T, Kouyos RD, Kovari H, Kusejko K
387 (Head of Data Centre), Labhardt N, Leuzinger K, Martinez de Tejada B, Marzolini C, Metzner KJ,
388 Müller N, Nemeth J, Nicca D, Notter J, Paioni P, Pantaleo G, Perreau M, Rauch A (Chairman of the
389 Scientific Board), Salazar-Vizcaya L, Schmid P, Speck R, Stöckle M (Chairman of the Clinical and
390 Laboratory Committee), Tarr P, Trkola A, Wandeler G, Weisser M, Yerly S.

391

392 The multi-centre study group, EuroSIDA (national coordinators in parenthesis).

393 Albania: (A Harxhi), University Hospital Center of Tirana, Tirana.

394 Argentina: (M Losso), M Kundro, Hospital JM Ramos Mejia, Buenos Aires.

395 Austria: (B Schmied), Klinik Penzing, Vienna; R Zangerle, Medical University Innsbruck, Innsbruck.

396 Belarus: (I Karpov), A Vassilenko, Belarusian State Medical University, Minsk; VM Mitsura, Gomel
397 State Medical University, Gomel; D Paduto, Regional AIDS Centre, Svetlogorsk.

398 Belgium: (N Clumeck), S De Wit, M Delforge, Saint-Pierre Hospital, Brussels; E Florence, Institute of
399 Tropical Medicine, Antwerp; L Vandekerckhove, University Ziekenhuis Gent, Gent.

400 Bosnia-Herzegovina: (V Hadziosmanovic), Klinicki Centar Univerziteta Sarajevo, Sarajevo.

401 Croatia: (J Begovac), University Hospital of Infectious Diseases, Zagreb.

402 Czech Republic: (L Machala), D Jilich, Faculty Hospital Bulovka, Prague; D Sedlacek, Charles
403 University Hospital, Plzen.

404 Denmark: G Kronborg, T Benfield, Hvidovre Hospital, Copenhagen; J Gerstoft, O Kirk, Rigshospitalet,
405 Copenhagen; C Pedersen, IS Johansen, Odense University Hospital, Odense; L Ostergaard, Skejby
406 Hospital, Aarhus, L Wiese, Sjællands Universitetshospital, Roskilde; L N Nielsen, Hillerod Hospital,
407 Hillerod.
408 Estonia: (K Zilmer), West-Tallinn Central Hospital, Tallinn; Jelena Smidt, Nakkusosakond Siseklinik,

409 Kohtla-Järve.

410 Finland: (I Aho), Helsinki University Hospital, Helsinki.

411 France: (J-P Viard), Hôtel-Dieu, Paris; K Lacombe, Hospital Saint-Antoine, Paris; C Pradier, E Fontas,

412 Hôpital de l'Archet, Nice; C Duvivier, Hôpital Necker-Enfants Malades, Paris.

413 Germany: (J Rockstroh), Universitäts Klinik Bonn; O Degen, University Medical Center Hamburg-

414 Eppendorf, Infectious Diseases Unit, Hamburg; C Hoffmann, HJ Stellbrink, ICH Study Center GmbH

415 & Co. KG, Hamburg; C Stefan, JW Goethe University Hospital, Frankfurt; J Bogner, Medizinische

416 Poliklinik, Munich; G. Fätkenheuer, Universität Köln, Cologne.

417 Georgia: (N Chkhartishvili) Infectious Diseases, AIDS & Clinical Immunology Research Center, Tbilisi.

418 Greece: (H Sambatakou), Ippokration General Hospital, Athens; G Adamis, N Paissios, Athens

419 General Hospital "G Gennimatas", Athens.

420 Hungary: (J Szlávik), South-Pest Hospital Centre – National Institute for Infectology and

421 Haematology, Budapest.

422 Iceland: (M Gottfredsson), Landspitali University Hospital, Reykjavik.

423 Ireland: (E Devitt), St. James's Hospital, Dublin.

424 Israel: (L Tau), D Turner, M Burke, Ichilov Hospital, Tel Aviv; E Shahar, LM Wattad, Rambam Health

425 Care Campus, Haifa; H Elinav, M Haouzi, Hadassah University Hospital, Jerusalem; D Elbirt, AIDS

426 Center (Neve Or), Rehovot.

427 Italy: (A D'Arminio Monforte), Istituto Di Clinica Malattie Infettive e Tropicale, Milan; G Guaraldi, R

428 Esposito, I Mazeu, C Mussini, Università Modena, Modena; F Mazzotta, A Gabbuti, Ospedale S Maria

429 Annunziata, Firenze; A Lazzarin, A Castagna, N Gianotti, Ospedale San Raffaele, Milan; M Galli, A

430 Ridolfo, Osp. L. Sacco, Milan.

431 Lithuania: (V Uzdaviniene) Vilnius University Hospital Santaros Klinikos, Vilnius; R Matulionyte,

432 Vilnius University, Faculty of Medicine, Department of Infectious Diseases and Dermatovenerology,

433 Vilnius.

434 Luxembourg: (T Staub), R Hemmer, Centre Hospitalier, Luxembourg.

435 Netherlands: (Marc vd Valk), Academisch Medisch Centrum bij de Universiteit van Amsterdam,

436 Amsterdam.
437 North Macedonia (J Trajanovska), University Clinic for Infectious Diseases & Febrile Conditions,

438 Mother Teresa 17, Skopje.

439 Norway: (DH Reikvam), A Maeland, J Bruun, Oslo University Hospital, Ullevaal.

440 Poland: (B Knysz), B Szetela, M Inglot, Medical University, Wroclaw; E Bakowska, Centrum

441 Diagnostyki i Terapii AIDS, Warsaw; R Flisiak, A Grzeszczuk, Medical University, Bialystok; M

442 Parczewski, K Maciejewska, B Aksak-Was, Medical University, Szczecin; M Beniowski, E Mularska,

443 Osrodek Diagnostyki i Terapii AIDS, Chorzow; E Jablonowska, J Kamerys, K Wojcik, Wojewodzki

444 Szpital Specjalistyczny, Lodz; I Mozer-Lisewska, B Rozplochowski, Poznan University of Medical

445 Sciences, Poznan.

446 Portugal: (A Zagalo), Hospital Santa Maria, Lisbon; K Mansinho, Hospital de Egas Moniz, Lisbon; F

447 Maltez, Hospital Curry Cabral, Lisbon.

448 Romania: (R Radoi), C Oprea, Carol Davila University of Medicine and Pharmacy Bucharest, Victor

449 Babes Clinical Hospital for Infectious and Tropical Diseases, Bucharest.

450 Russia: D Gusev, Medical Academy Botkin Hospital, St Petersburg; T Trofimova, Novgorod Centre for

451 AIDS, Novgorod, I Khromova, Centre for HIV/AIDS & and Infectious Diseases, Kaliningrad; E

452 Kuzovatova, Academician I.N.Blokhina Nizhny Novgorod Scientific Research Institute of

453 Epidemiology and Microbiology, Nizhny Novgorod; E Borodulina, E Vdoushkina, Samara State

454 Medical University, Samara.

455 Serbia: (J Ranin), The Institute for Infectious and Tropical Diseases, Belgrade.

456 Slovenia: (J Tomazic), University Clinical Centre Ljubljana, Ljubljana.

457 Spain: (JM Miro), JM Miró, M. Laguno, E. Martinez, F. Garcia, JL Blanco, M. Martinez-Rebollar, J.

458 Mallolas, P Callau, J Rojas, A Inciarta, Hospital Clinic - IDIBAPS University of Barcelona, Barcelona;

459 S Moreno, S. del Campo, Hospital Ramon y Cajal, Madrid; B Clotet, A Jou, R Paredes, J Puig, JM

460 Llibre, JR Santos, Infectious Diseases Unit & IrsiCaixa AIDS Research Institute, Hospital Germans

461 Trias I Pujol, Badalona; P Domingo, M Gutierrez, G Mateo, MA Sambeat, Hospital Sant Pau,

462 Barcelona; JM Laporte, Hospital Universitario de Alava, Vitoria-Gasteiz.

463 Sweden: (P Novak), A Thalme, A Sönnerborg, Karolinska University Hospital, Stockholm; J

464 Brännström, Venhälsan-Sodersjukhuset, Stockholm; L Flamholc, Malmö University Hospital, Malmö.
465 Switzerland: (K Kusejko), D Braun, University Hospital Zurich; M Cavassini, University Hospital

466 Lausanne; A Calmy, University Hospital Geneva; H Furrer, University Hospital Bern; M Battegay,

467 University Hospital Basel; P Schmid, Cantonal Hospital St. Gallen.

468 Ukraine: A Kuznetsova, Kharkov State Medical University, Kharkov; J Mikhalik, Crimean Republican

469 AIDS centre, Simferopol; M Sluzhynska, Lviv Regional HIV/AIDS Prevention and Control CTR, Lviv.

470 United Kingdom: A Milinkovic, St. Stephen's Clinic, Chelsea and Westminster Hospital, London; AM

471 Johnson, S Edwards, Mortimer Market Centre, London; A Phillips, MA Johnson, A Mocroft, Royal

472 Free and University College Medical School, London (Royal Free Campus); C Orkin, Royal London

473 Hospital, London; A Winston, Imperial College School of Medicine at St. Mary's, London; A Clarke,

474 Royal Sussex County Hospital, Brighton; C. Mackintosh, C Leen, Western General Hospital,

475 Edinburgh.

476

477 The following centers have previously contributed data to EuroSIDA:

478 Medical University, Gdansk, Poland

479 Infectious Diseases Hospital, Sofia, Bulgaria

480 Hôpital de la Croix Rousse, Lyon, France

481 Hôpital de la Pitié-Salpétière, Paris, France

482 Unité INSERM, Bordeaux, France

483 Hôpital Edouard Herriot, Lyon, France

484 Bernhard Nocht Institut für Tropenmedizin, Hamburg, Germany

485 1st I.K.A Hospital of Athens, Athens, Greece

486 Ospedale Riuniti, Divisione Malattie Infettive, Bergamo, Italy

487 Ospedale di Bolzano, Divisione Malattie Infettive, Bolzano, Italy

488 Ospedale Cotugno, III Divisione Malattie Infettive, Napoli, Italy

489 Dérer Hospital, Bratislava, Slovakia

490 Hospital Carlos III, Departamento de Enfermedades Infecciosas, Madrid, Spain

491 Kiev Centre for AIDS, Kiev, Ukraine

492 Luhansk State Medical University, Luhansk, Ukraine

493 Odessa Region AIDS Center, Odessa, Ukraine

494 St Petersburg AIDS Centre, St Petersburg, Russia
495 Infectology Centre of Latvia, Riga, Latvia

496 University di Roma la Sapienza, Rome, Italy

497 Istituto Nazionale Malattie Infettive Lazzaro Spallanzani, Rome, Italy

498

499 **EuroSIDA Steering Committee**

500 Steering Committee: I Karpov, M Losso, J Lundgren, J Rockstroh, I Aho, LD Rasmussen, P Novak, G

501 Wandeler, C Pradier, N Chkhartishvili, R Matulionyte, C Oprea, JD Kowalska, J Begovac, JM Miró, G

502 Guaraldi, R Paredes

503 Chair: G Wandeler

504 Co-Chair: R Paredes

505 Study lead: L Peters

506

507 **EuroSIDA staff**

508 Coordinating Centre Staff: L Peters, JF Larsen, B Neesgaard, N Jaschinski, O Fursa, D Raben, D

509 Kristensen, AH Fischer, SK Jensen, TW Elsing, M Gardizi

510 Statistical Staff: A Mocroft, A Phillips, J Reekie, A Cozzi-Lepri, A Pelchen-Matthews, A Roen, ES

511 Tusch, W Bannister

512

513 **ATHENA cohort**

514 **Amsterdam UMC, AMC site, Amsterdam: HIV treating physicians:** M. van der Valk, S.E. Geerlings,

515 A. Goorhuis, V.C. Harris, J.W. Hovius, B. Lempkes, F.J.B. Nellen, T. van der Poll, J.M. Prins, V.

516 Spoorenberg, M. van Vugt, W.J. Wiersinga, F.W.M.N. Wit. **HIV nurse consultants:** C. Bruins, J. van

517 Eden, I.J. Hylkema-van den Bout, A.M.H. van Hes, F.J.J. Pijnappel, S.Y. Smalhout, A.M. Weijsenfeld.

518 **HIV clinical virologists/chemists:** N.K.T. Back, B. Berkhout, M.T.E. Cornelissen, R. van Houdt, M.

519 Jonges, S. Jurriaans, C.J. Schinkel, K.C. Wolthers, H.L. Zaaijer. **Amsterdam UMC, VUmc site,**

520 **Amsterdam: HIV treating physicians:** E.J.G. Peters, M.A. van Agtmael, R.S. Autar, M. Bomers,

521 K.C.E. Sigaloff. **HIV nurse consultants:** M. Heitmuller, L.M. Laan. **HIV clinical virologists/chemists:**

522 N.K.T. Back, B. Berkhout, M.T.E. Cornelissen, R. van Houdt, M. Jonges, S. Jurriaans, C.J. Schinkel,

523 K.C. Wolthers, H.L. Zaaijer. **Admiraal De Ruyter Ziekenhuis, Goes:** **HIV treating physicians:** M. van

524 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,
555 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.

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557 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.

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560 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.

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Berk, K.D. Lettinga, M. de Regt, W.E.M. Schouten, J.E. Stalenhoef, J. Veenstra, S.M.E. Vrouenraets.

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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.

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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.

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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.

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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.

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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.

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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.

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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.M. 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.

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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.

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584
585 **Coordinating center Board of directors**: M. van der Valk, S. Zaheri. *HIV data analysis*: A.C. Boyd,

586 D.O. Bezemer, A.I. van Sighem, C. Smit, F.W.M.N. Wit. *Data HIV data management and quality*

587 *control*: M.M.J. Hillebregt, T.J. Woudstra, T. Rutkens. *HIV data monitoring*: D. Bergsma, N.M. Brétin,

588 K.J. Lelivelt, L. van de Sande, K.M. Visser. S.T. van der Vliet. *HIV data collection*: F. Paling, L.G.M.

589 de Groot-Berndsen, M. van den Akker, R. Alexander, Y. Bakker, A. El Berkaoui, M. Bezemer-

590 Goedhart, E.A. Djoechro, M. Groters, L.E. Koster, C.R.E. Lodewijk, E.G.A. Lucas, L. Munjishvili, B.M.

591 Peeck, C.M.J. Ree, R. Regtop, A.F. van Rijk, Y.M.C. Ruijs-Tiggelman, P.P. Schnörr, M.J.C. Schoorl,

592 E.M Tuijn, D.P. Veenenberg, E.C.M Witte. *Patiënt registration*: D. Bergsma, N.M. Brétin, Y.M.C. Ruijs-

593 Tiggelman.

594

595 **ANRS CO3 AQUITAINE - AquiVIH-NA**

596 **Cohort scientific committee**: P. Bellecave, P. Blanco, F. Bonnet (Chair), S. Bouchet, D. Breilh, C.

597 Cazanave, S. Desjardin, V. Gaborieau, A. Gimbert, M. Hessamfar, L. Lacaze-Buzy, D. Lacoste, ME

598 Lafon, E. Lazaro, O. Leleux., F. Le Marec, G. Le Moal, D. Malvy, L. Marchand, P. Mercié, D. Neau, I.

599 Pellegrin, A. Perrier, V. Petrov-Sanchez, M.O. Vareil, L. Wittkop (Methodologist).

600 **Participating centers**: Hôpital Saint André, CHU de Bordeaux, Médecine Interne et Maladies

601 Infectieuses, (N. Bernard, F. Bonnet, D. Bronnimann H. Chaussade, D. Dondia, P. Duffau, I. Faure,

602 M. Hessamfar, P Mercié, P. Morlat, E. Mériglier, F. Paccalin, E. Riebero, C. Rivoisy, MA

603 Vandenhende) ; Hôpital Pellegrin, CHU de Bordeaux, Maladies Infectieuses et Tropicales, (L.

604 Barthod, C. Cazanave, FA. Dauchy, A. Desclaux, M. Ducours, H. Dutronc, A. Duvignaud, J. Leitao, M.

605 Lescure, D. Neau, D. Nguyen, D. Malvy, T. Pistone, M. Puges, G. Wirth); Hôpital Haut-Lévêque, CHU

606 de Bordeaux, Médecine Interne et Maladies Infectieuses, (C. Courtault, F. Camou, C. Greib, E.

607 Lazaro, JL. Pellegrin, E. Rivière, JF. Viallard) ; Hôpital d'Agen, Médecine Interne (Y. Imbert, M.

608 Thierry-Mieg, P. Rispal) ; Hôpital de Libourne, Médecine Interne (O. Caubet, H. Ferrand, S.

609 Tchamgoué) ; Hôpital de Bayonne, Maladies Infectieuses (S. Farbos, MO. Vareil, H. Wille); Hôpital de

610 Dax, Médecine Interne et Maladies Infectieuses, (K. Andre, L. Caunegre, Y. Gerard, F. Osorio-Perez);

611 Hôpital Saint-Cyr/Villeneuve-sur-Lot, Maladies Infectieuses, (I. Chossat); Hôpital de Mont de Marsan,

612 Médecine Interne et Maladies Infectieuses, (G. Iles, Y. Gerard, M. Labasse-Depis, F. Lacassin);

613 Hôpital d'Arcachon, Médecine Interne, (A. Barret, C. Courtault); Hôpital de Périgueux, Médecine

614 Interne et Maladies Infectieuses, (B Castan, J. Koffi, N. Rouanes, A. Saunier, JB Zabbe); Hôpital de
615 Pau, Médecine Interne et Maladies Infectieuses, (G. Dumondin, V. Gaborieau); Hôpital d'Orthez,

616 Médecine Interne, (Y. Gerard) ; CHU de Poitiers, Médecine Interne et Maladies Infectieuses, (G.

617 Beraud, G. Le Moal, M. Catroux, M. Garcia, V. Giraud, JP. Martellosio, F. Roblot) ; Hôpital de Saintes,

618 Médecine Interne, (T. Pasdeloup) ; Hôpital d'Angoulême, Médecine Interne, (A. Riché, M. Grosset, S.

619 Males, C. Ngo Bell) ; Hôpital de Jonzac, Maladies Infectieuses, (T. Pasdeloup), Hôpital de Saint jean

620 d'Angely, Maladies Infectieuses, (T. Pasdeloup). Other departments: Immunology: P. Blanco, I.

621 Pellegrin ; CRB-BBS: C. Carpentier, I. Pellegrin ; Virology: P. Bellecave, ME. Lafon, C. Tumiotto ;

622 Pharmacology: S. Bouchet, D. Breilh, G. Miremeont-Salamé ; Data collection : D. Arma, G. Arnou, MJ

623 Blaizeau, P. Camps, M. Decoin, S. Delveaux, F. Diarra, L. Gabrea, S. Lawson-Ayayi, E. Lenaud, D.

624 Plainchamps, A. Pougetoux, B. Uwamaliya, K. Zara ; IT departement : V. Conte, M. Gapillout ; Project

625 Team : O. Leleux (Project Leader), F. Le Marec (Statistitien), A. Perrier (Data Manager).

626 **Website:** https://aquivih-na.fr

627
628 REFERENCES

629 Author names in bold designate shared co-first authorship.

630 [1] Perz JF, Armstrong GL, Farrington LA, Hutin YJF, Bell BP. The contributions of hepatitis B virus
631 and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol
632 2006;45:529-38. https://doi.org/10.1016/j.jhep.2006.05.013.

633 [2] Kanwal F, Singal AG. Surveillance for Hepatocellular Carcinoma: Current Best Practice and
634 Future Direction. Gastroenterology 2019;157:54-64.
635 https://doi.org/10.1053/j.gastro.2019.02.049.

636 [3] Costentin CE, Layese R, Bourcier V, Cagnot C, Marcellin P, Guyader D, et al. Compliance With
637 Hepatocellular Carcinoma Surveillance Guidelines Associated With Increased Lead-Time
638 Adjusted Survival of Patients With Compensated Viral Cirrhosis: A Multi-Center Cohort Study.
639 Gastroenterology 2018;155:431-442.e10. https://doi.org/10.1053/j.gastro.2018.04.027.

640 [4] Willemse S, Smit C, Sogni P, Sarcletti M, Uberti-Foppa C, Wittkop L, et al. Low compliance with
641 hepatocellular carcinoma screening guidelines in hepatitis B/C virus co-infected HIV patients with
642 cirrhosis. J Viral Hepat 2019;26:1224-8. https://doi.org/10.1111/jvh.13146.

643 [5] Patel N, Post FA. Surveillance for hepatocellular carcinoma in people of African ancestry with
644 HIV and Hepatitis B. Int J STD AIDS 2022;33:202-4.
645 https://doi.org/10.1177/09564624211042828.

646 [6] Wandeler G, Mauron E, Atkinson A, Dufour J-F, Kraus D, Reiss P, et al. Incidence of
647 hepatocellular carcinoma in HIV/HBV-coinfected patients on tenofovir therapy: Relevance for
648 screening strategies. J Hepatol 2019;71:274-80. https://doi.org/10.1016/j.jhep.2019.03.032.

649 [7] Papatheodoridis G, Dalekos G, Sypsa V, Yurdaydin C, Buti M, Goulis J, et al. PAGE-B predicts
650 the risk of developing hepatocellular carcinoma in Caucasians with chronic hepatitis B on 5-year
651 antiviral therapy. J Hepatol 2016;64:800-6. https://doi.org/10.1016/j.jhep.2015.11.035.

652 [8] European Association for the Study of the Liver (EASL). Clinical Practice Guidelines on the
653 management of hepatitis B virus infection. J Hepatol 2017;67:370-98.
654 https://doi.org/10.1016/j.jhep.2017.03.021.

655 [9] European AIDS Clinical Society (EACS). Guidelines for the management of people living with
656 HIV 2021. https://www.eacsociety.org/media/final2021eacsguidelinesv11.0_oct2021.pdf
657 (accessed February 25, 2022).
658

[10] **Scherrer AU, Traytel A**, Braun DL, Calmy A, Battegay M, Cavassini M, et al. Cohort Profile

659

Update: The Swiss HIV Cohort Study (SHCS). Int J Epidemiol 2022;51:33–34j.

660

https://doi.org/10.1093/ije/dyab141.

661

[11] Boender TS, Smit C, van Sighem A, Bezemer D, Ester CJ, Zaheri S, et al. AIDS Therapy

662

Evaluation in the Netherlands (ATHENA) national observational HIV cohort: cohort profile. BMJ

663

Open 2018;8:e022516. https://doi.org/10.1136/bmjopen-2018-022516.

664

[12] Collin A, Le Marec F, Vandenhende M-A, Lazaro E, Duffau P, Cazanave C, et al. Incidence and

665

Risk Factors for Severe Bacterial Infections in People Living with HIV. ANRS CO3 Aquitaine

666

Cohort, 2000-2012. PLoS One 2016;11:e0152970. https://doi.org/10.1371/journal.pone.0152970.

667

[13] Laut K, Kirk O, Rockstroh J, Phillips A, Ledergerber B, Gatell J, et al. The EuroSIDA study: 25

668

years of scientific achievements. HIV Med 2020;21:71–83. https://doi.org/10.1111/hiv.12810.

669

[14] Collins GS, Reitsma JB, Altman DG, Moons KGM. Transparent Reporting of a multivariable

670

prediction model for Individual Prognosis or Diagnosis (TRIPOD): the TRIPOD statement. Ann

671

Intern Med 2015;162:55–63. https://doi.org/10.7326/M14-0697.

672

[15] Royston P, Altman DG. External validation of a Cox prognostic model: principles and methods.

673

BMC Med Res Methodol 2013;13:33. https://doi.org/10.1186/1471-2288-13-33.

674

[16] Heimbach JK, Kulik LM, Finn RS, Sirlin CB, Abecassis MM, Roberts LR, et al. AASLD guidelines

675

for the treatment of hepatocellular carcinoma. Hepatology 2018;67:358–80.

676

https://doi.org/10.1002/hep.29086.

677

[17] Blanche P, Dartigues J-F, Jacqmin-Gadda H. Estimating and comparing time-dependent areas

678

under receiver operating characteristic curves for censored event times with competing risks.

679

Stat Med 2013;32:5381–97. https://doi.org/10.1002/sim.5958.

680

[18] van Buuren S, Groothuis-Oudshoorn K. mice: Multivariate Imputation by Chained Equations in R.

681

J Stat Softw 2011;45:1–67. https://doi.org/10.18637/jss.v045.i03.

682

[19] Rubin DB. Multiple Imputation for Nonresponse in Surveys. Wiley; 1987.

683

https://doi.org/10.1002/9780470316696.

684

[20] Marshall A, Altman DG, Holder RL, Royston P. Combining estimates of interest in prognostic

685

modelling studies after multiple imputation: current practice and guidelines. BMC Med Res

686

Methodol 2009;9:57. https://doi.org/10.1186/1471-2288-9-57.
687 [21] R Core Team. R: A Language and Environment for Statistical Computing 2022. https://www.R-project.org/ (accessed April 4, 2022).

688 [22] Wickham H, Averick M, Bryan J, Chang W, McGowan L, François R, et al. Welcome to the tidyverse. J Open Source Softw 2019;4:1686. https://doi.org/10.21105/joss.01686.

691 [23] Yang JD, Gyedu A, Afihene MY, Duduyemi BM, Micah E, Kingham TP, et al. Hepatocellular Carcinoma Occurs at an Earlier Age in Africans, Particularly in Association With Chronic Hepatitis B. Am J Gastroenterol 2015;110:1629-31. https://doi.org/10.1038/ajg.2015.289.

695 [24] European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol 2018;69:182-236. https://doi.org/10.1016/j.jhep.2018.03.019.

697 [25] Brouwer WP, van der Meer AJP, Boonstra A, Plompen EPC, Pas SD, de Knegt RJ, 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;24:1023-31. https://doi.org/10.1111/jvh.12727.

700 [26] Kim MN, Hwang SG, Rim KS, Kim BK, Park JY, Kim DY, et al. Validation of PAGE-B model in Asian chronic hepatitis B patients receiving entecavir or tenofovir. Liver Int 2017;37:1788-95. https://doi.org/10.1111/liv.13450.

703 [27] Yip TC-F, Wong GL-H, Wong VW-S, Tse Y-K, Liang LY, Hui VW-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;72:847-54. https://doi.org/10.1016/j.jhep.2019.12.005.

706 [28] Kim HN, Newcomb CW, Carbonari DM, Roy JA, Torgersen J, Althoff KN, et al. Risk of HCC With Hepatitis B Viremia Among HIV/HBV-Coinfected Persons in North America. Hepatology 2021;74:1190-202. https://doi.org/10.1002/hep.31839.

709 [29] Yang JD, Altekruse SF, Nguyen MH, Gores GJ, Roberts LR. Impact of country of birth on age at the time of diagnosis of hepatocellular carcinoma in the United States. Cancer 2017;123:81-9. https://doi.org/10.1002/cncr.30246.

712 [30] Yang JD, Mohamed EA, Aziz AOA, Shousha HI, Hashem MB, Nabeel MM, 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;2:103-11. https://doi.org/10.1016/S2468-1253(16)30161-3.
716

[31] Collins GS, Ogundimu EO, Altman DG. Sample size considerations for the external validation of a multivariable prognostic model: a resampling study. Stat Med 2016;35:214–26.

717

718

https://doi.org/10.1002/sim.6787.

719

[32] 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;66:297–303.

720

721

https://doi.org/10.1016/j.jhep.2016.10.007.

722
723 TABLES

724 Table 1 Patient characteristics at tenofovir start, stratified by cohort

<table><thead><tr><th>Characteristic</th><th>Overall (n = 2963)</th><th>Aquitaine (n = 337)</th><th>ATHENA (n = 1319)</th><th>EuroSIDA (n = 800)</th><th>SHCS (n = 507)</th></tr></thead><tbody><tr><td>Male sex</td><td>2477 (84%)</td><td>277 (82%)</td><td>1147 (87%)</td><td>662 (83%)</td><td>391 (77%)</td></tr><tr><td>Age in years (IQR)</td><td>41 (35 to 47)</td><td>42 (37 to 48)</td><td>41 (35 to 48)</td><td>41 (36 to 47)</td><td>40 (35 to 46)</td></tr><tr><td>Caucasian</td><td>2023 (68%)</td><td>289 (86%)</td><td>774 (59%)</td><td>641 (80%)</td><td>319 (63%)</td></tr><tr><td>(Missing)</td><td>69 (2.3%)</td><td>3 (0.9%)</td><td>8 (0.6%)</td><td>58 (7.2%)</td><td>0 (0%)</td></tr><tr><td>Region of Origin</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>European or USA</td><td>2023 (68%)</td><td>289 (86%)</td><td>774 (59%)</td><td>641 (80%)</td><td>319 (63%)</td></tr><tr><td>African</td><td>525 (18%)</td><td>41 (12%)</td><td>293 (22%)</td><td>56 (7.0%)</td><td>135 (27%)</td></tr><tr><td>Latin American</td><td>162 (5.5%)</td><td>1 (0.3%)</td><td>148 (11%)</td><td>0 (0%)</td><td>13 (2.6%)</td></tr><tr><td>Asian</td><td>155 (5.2%)</td><td>3 (0.9%)</td><td>96 (7.3%)</td><td>18 (2.2%)</td><td>38 (7.5%)</td></tr><tr><td>Other</td><td>29 (1.0%)</td><td>0 (0%)</td><td>0 (0%)</td><td>27 (3.4%)</td><td>2 (0.4%)</td></tr><tr><td>Unknown</td><td>69 (2.3%)</td><td>3 (0.9%)</td><td>8 (0.6%)</td><td>58 (7.2%)</td><td>0 (0%)</td></tr><tr><td>Transmission Group</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>MSM</td><td>1536 (52%)</td><td>159 (49%)</td><td>820 (67%)</td><td>330 (41%)</td><td>227 (47%)</td></tr><tr><td>PWID</td><td>412 (14%)</td><td>62 (19%)</td><td>41 (3.3%)</td><td>234 (29%)</td><td>75 (15%)</td></tr><tr><td>Heterosexual</td><td>783 (26%)</td><td>98 (30%)</td><td>350 (29%)</td><td>156 (20%)</td><td>179 (37%)</td></tr><tr><td>Other</td><td>50 (1.7%)</td><td>8 (2.4%)</td><td>16 (1.3%)</td><td>19 (2.4%)</td><td>7 (1.4%)</td></tr><tr><td>(Missing)</td><td>182 (6.1%)</td><td>10 (3.0%)</td><td>92 (7.0%)</td><td>61 (7.6%)</td><td>19 (3.7%)</td></tr><tr><td>HIV Viral Load</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>≥ 200 cp/mL</td><td>1596 (54%)</td><td>146 (43%)</td><td>780 (59%)</td><td>382 (48%)</td><td>288 (57%)</td></tr><tr><td>50 – 199 cp/mL</td><td>190 (6.5%)</td><td>21 (6.2%)</td><td>88 (6.7%)</td><td>57 (7.1%)</td><td>24 (4.7%)</td></tr><tr><td>Below 50 cp/mL</td><td>1018 (34%)</td><td>112 (33%)</td><td>419 (32%)</td><td>298 (37%)</td><td>189 (37%)</td></tr><tr><td>(Missing)</td><td>159 (5.4%)</td><td>58 (17%)</td><td>32 (2.4%)</td><td>63 (7.9%)</td><td>6 (1.2%)</td></tr><tr><td>BMI in kg/m²</td><td>22.8 (20.8 to 25.1)</td><td>22.3 (20.4 to 24.6)</td><td>22.9 (20.9 to 25.0)</td><td>22.7 (20.8 to 25.1)</td><td>23.0 (20.8 to 25.8)</td></tr><tr><td>(Missing)</td><td>639 (22%)</td><td>92 (27%)</td><td>185 (14%)</td><td>317 (40%)</td><td>45 (8.9%)</td></tr><tr><td>CD4 cell count, cells/µL (IQR)</td><td>323 (182 to 510)</td><td>376 (196 to 584)</td><td>310 (170 to 490)</td><td>346 (210 to 531)</td><td>314 (198 to 472)</td></tr><tr><td>(Missing)</td><td>181 (6.1%)</td><td>60 (18%)</td><td>32 (2.4%)</td><td>83 (10%)</td><td>6 (1.2%)</td></tr><tr><td>Diabetes</td><td>183 (6.2%)</td><td>38 (11%)</td><td>82 (6.2%)</td><td>39 (4.9%)</td><td>24 (4.7%)</td></tr><tr><td>Liver cirrhosis</td><td>314 (11%)</td><td>27 (9.9%)</td><td>129 (15%)</td><td>94 (12%)</td><td>64 (16%)</td></tr><tr><td>ALT at baseline in IU/L (IQR)</td><td>41 (25 to 79)</td><td>38 (24 to 70)</td><td>47 (26 to 134)</td><td>39 (25 to 69)</td><td>39 (25 to 65)</td></tr><tr><td>(Missing)</td><td>731 (25%)</td><td>60 (18%)</td><td>444 (34%)</td><td>191 (24%)</td><td>36 (7.1%)</td></tr><tr><td>Platelets in G/L (IQR)</td><td>190 (141 to 236)</td><td>194 (144 to 235)</td><td>188 (133 to 235)</td><td>192 (152 to 233)</td><td>190 (148 to 239)</td></tr><tr><td>(Missing)</td><td>1063 (36%)</td><td>76 (23%)</td><td>560 (42%)</td><td>406 (51%)</td><td>21 (4.1%)</td></tr><tr><td>Platelet count category</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>≥ 200 G/L</td><td>859 (25%)</td><td>121 (36%)</td><td>347 (26%)</td><td>175 (22%)</td><td>216 (43%)</td></tr><tr><td>100-199 G/L</td><td>828 (28%)</td><td>102 (30%)</td><td>325 (25%)</td><td>179 (22%)</td><td>222 (46%)</td></tr><tr><td>&lt;100 G/L</td><td>213 (7.2%)</td><td>38 (11%)</td><td>87 (6.6%)</td><td>40 (5%)</td><td>48 (9.5%)</td></tr><tr><td>(Missing)</td><td>1063 (36%)</td><td>76 (23%)</td><td>560 (42%)</td><td>406 (51%)</td><td>21 (4.1%)</td></tr><tr><td>HDV coinfection</td><td>147 (5%)</td><td>15 (17%)</td><td>13 (9.4%)</td><td>69 (8.6%)</td><td>50 (11%)</td></tr><tr><td>(Missing)</td><td>1941 (66%)</td><td>250 (74%)</td><td>1180 (89%)</td><td>451 (56%)</td><td>60 (12%)</td></tr><tr><td>HCV coinfection</td><td>274 (9.2%)</td><td>22 (6.5%)</td><td>51 (3.9%)</td><td>157 (20%)</td><td>44 (8.7%)</td></tr><tr><td>HBeAg-positivity</td><td>799 (27%)</td><td>106 (50%)</td><td>515 (45%)</td><td>26 (3.2%)</td><td>152 (55%)</td></tr><tr><td>(Missing)</td><td>1277 (43%)</td><td>124 (37%)</td><td>167 (13%)</td><td>756 (94%)</td><td>230 (45%)</td></tr><tr><td>XTC use before TFV</td><td>1629 (55%)</td><td>211 (63%)</td><td>584 (44%)</td><td>550 (69%)</td><td>284 (56%)</td></tr><tr><td>Prior XTC in years (IQR)</td><td>3.7 (0.0 to 8.2)</td><td>3.8 (0.0 to 7.2)</td><td>0.0 (0.0 to 6.0)</td><td>5.2 (0.0 to 8.1)</td><td>9.9 (5.2 to 15.1)</td></tr><tr><td>Follow-up on TFV in years (IQR)</td><td>9.6 (4.9 to 13.3)</td><td>10.8 (5.6 to 15.0)</td><td>9.7 (5.3 to 13.1)</td><td>8.4 (3.8 to 12.3)</td><td>10.3 (5.2 to 14.3)</td></tr></tbody></table>
<table><thead><tr><th>Characteristic</th><th>Overall<br>(n = 2963)</th><th>Aquitaine<br>(n = 337)</th><th>ATHENA<br>(n = 1319)</th><th>EuroSIDA<br>(n = 800)</th><th>SHCS<br>(n = 507)</th></tr></thead><tbody><tr><td>IQR</td><td colspan="5">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.</td></tr></tbody></table>

725

726
727

**Table 2** Life table comparison of hepatocellular carcinoma (HCC) cases in the present study and the original derivation study

728

729

<table><thead><tr><th rowspan="2">PAGE-B<br>Category</th><th rowspan="2">Years</th><th colspan="2">N at risk</th><th colspan="2">Cumulative N<br>(Cumulative Incidence)<br>of HCCs</th><th colspan="2">Cumulative Incidence of<br>Original Publication<sup>1</sup></th></tr><tr><th>Complete<br>case</th><th>Imputation</th><th>Complete case</th><th>Imputation</th><th>Derivation</th><th>Validation</th></tr></thead><tbody><tr><td rowspan="6">Score &lt;10</td><td>1</td><td>480</td><td>734</td><td>1 (0.2%)</td><td>1 (0.1%)</td><td>0%</td><td>0%</td></tr><tr><td>2</td><td>449</td><td>694</td><td>1 (0.2%)</td><td>1 (0.1%)</td><td>0%</td><td>0%</td></tr><tr><td>3</td><td>412</td><td>651</td><td>1 (0.2%)</td><td>1 (0.1%)</td><td>0%</td><td>0%</td></tr><tr><td>5</td><td>357</td><td>573</td><td>2 (0.5%)</td><td>2 (0.3%)</td><td>0%</td><td>0%</td></tr><tr><td>10</td><td>216</td><td>358</td><td>2 (0.5%)</td><td>2 (0.3%)</td><td>n.r.</td><td>n.r.</td></tr><tr><td>15</td><td>79</td><td>131</td><td>4 (2.5%)</td><td>4 (1.5%)</td><td>n.r.</td><td>n.r.</td></tr><tr><td rowspan="6">Score 10-17</td><td>1</td><td>1001</td><td>1625</td><td>1 (0.1%)</td><td>1 (0.1%)</td><td>0%</td><td>0%</td></tr><tr><td>2</td><td>937</td><td>1534</td><td>3 (0.3%)</td><td>8 (0.5%)</td><td>1%</td><td>1%</td></tr><tr><td>3</td><td>877</td><td>1442</td><td>5 (0.5%)</td><td>10 (0.6%)</td><td>1%</td><td>1%</td></tr><tr><td>5</td><td>794</td><td>1319</td><td>8 (0.9%)</td><td>14 (0.9%)</td><td>3%</td><td>4%</td></tr><tr><td>10</td><td>490</td><td>863</td><td>13 (1.6%)</td><td>21 (1.5%)</td><td>n.r.</td><td>n.r.</td></tr><tr><td>15</td><td>147</td><td>279</td><td>15 (2.2%)</td><td>26 (2.3%)</td><td>n.r.</td><td>n.r.</td></tr><tr><td rowspan="6">Score ≥18</td><td>1</td><td>268</td><td>426</td><td>5 (1.8%)</td><td>6 (1.4%)</td><td>3%</td><td>3%</td></tr><tr><td>2</td><td>247</td><td>396</td><td>8 (2.9%)</td><td>9 (2.1%)</td><td>6%</td><td>5%</td></tr><tr><td>3</td><td>217</td><td>356</td><td>12 (4.6%)</td><td>15 (3.7%)</td><td>9%</td><td>8%</td></tr><tr><td>5</td><td>185</td><td>311</td><td>14 (5.6%)</td><td>20 (5.2%)</td><td>17%</td><td>16%</td></tr><tr><td>10</td><td>92</td><td>175</td><td>22 (11.2%)</td><td>32 (10.1%)</td><td>n.r.</td><td>n.r.</td></tr><tr><td>15</td><td>28</td><td>52</td><td>24 (14.4%)</td><td>38 (16.0%)</td><td>n.r.</td><td>n.r.</td></tr></tbody></table>

N = Number, HCC = hepatocellular carcinoma, n.r. = not reported

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<footnote n="1">¹Papathodoridis 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.</footnote>
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# FIGURES

Complete Case Dataset

<figure><img src="image_10.png" /><figcaption>(B) Hepatocellular Carcinoma Cases</figcaption></figure>

Imputation Dataset

<figure><img src="image_11.png" /><figcaption>(D) Hepatocellular Carcinoma Cases</figcaption></figure>

<figure><img src="image_12.png" /></figure>

<figure><img src="image_13.png" /></figure>

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<caption>**Figure 1 Distribution of PAGE-B scores and hepatocellular carcinoma cases**</caption>

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Distribution of available PAGE-B scores in the complete case data (A) and after multiple imputation

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(C). Hepatocellular carcinoma cases by PAGE-B score are represented as dots in the complete case

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data (B) and after multiple imputation (D).

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<figure><img src="image_14.png" /><figcaption>Figure 2 Cumulative incidence of hepatocellular carcinoma since tenofovir start</figcaption></figure>

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)
<figure><img src="image_15.png" /><figcaption>Figure 3 Fifteen-year probability of developing hepatocellular carcinoma, by PAGE-B score</figcaption></figure>

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.
(A) Full Dataset

(B) Non-African Individuals

Cumulative 15-Year HCC-Risk

<figure><img src="image_16.png" /></figure>

PAGE-B: 12

<figure><img src="image_17.png" /></figure>

PAGE-B: 13
<figure><img src="image_18.png" /><figcaption>(A) Distribution of Page-B Values</figcaption></figure>

<figure><img src="image_19.png" /><figcaption>(C) Distribution of Page-B Values</figcaption></figure>

<figure><img src="image_20.png" /><figcaption>(B) Hepatocellular Carcinoma Cases</figcaption></figure>

<figure><img src="image_21.png" /><figcaption>(D) Hepatocellular Carcinoma Cases</figcaption></figure>
(A) Full Dataset

Journal Pre-proof

<figure><img src="image_22.png" /></figure>

(B) Non-African Individuals

<figure><img src="image_23.png" /></figure>

No. at risk

<table><tr><td>PAGE-B &lt; 10</td><td>785</td><td>573</td><td>358</td><td>131</td></tr><tr><td>PAGE-B 11-17</td><td>1711</td><td>1319</td><td>863</td><td>279</td></tr><tr><td>PAGE-B ≥ 18</td><td>466</td><td>311</td><td>175</td><td>52</td></tr></table>

<table><tr><td>497</td><td>364</td><td>235</td><td>89</td></tr><tr><td>1513</td><td>1182</td><td>781</td><td>250</td></tr><tr><td>427</td><td>281</td><td>164</td><td>56</td></tr></table>
1 **External validation of the PAGE-B score to estimate the risk of**
2 **hepatocellular carcinoma in persons living with HIV and hepatitis B**

3

4 Benrard Surial et al.

5

6 Highlights

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* This external validation study included 2963 individuals with HIV/HBV coinfection from 4
European cohorts.

9
* Within a median of 9.6 years, 68 patients developed hepatocellular carcinoma (incidence rate
2.58/1000 person-years).

10

11
* Among individuals with HIV/HBV coinfection, PAGE-B (based on age, sex and platelets) showed
good model discrimination.

12

13
* A PAGE-B score <10 had a negative predictive value of 99.4% for developing hepatocellular
carcinoma within 5 years.

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