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External validation of the PAGE-B score for
HCC risk prediction in people living with HIV/HBV coinfection
  January 20, 2023
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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 [[1]]. 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 [[2],[3]]. However, screening uptake remains suboptimal, and therefore represents a missed opportunity to prevent HCC-related deaths [[4],[5]]. 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 [[6]]. 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 [[7]]. 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) [[8]]. 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 [[9]], 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 [[6]].
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.
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 [[7]], 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 [[24]]. 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 [[7]]. 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 [[25],[26]]. 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 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.


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

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