Novel serum biomarkers for risk stratification in chronic hepatitis B-what do they bring to the table?

Louise Downs, Marion Delphin, Tingyan Wang, Cori Campbell, Sheila Lumley, Elizabeth Waddilove, Catherine De Lara, Sue Wareing, Polly Fengou, Kosh Agarwal

Research output: Contribution to journalMeeting AbstractAcademic

Abstract

Background and aims: Chronic hepatitis B infection (CHB) has diverseclinical phenotypes.HepatitisBcore relatedantigen(HBcrAg) and pre-genomic RNA (pgRNA) are novel serum biomarkers that provide a proxy signal for cccDNA transcription. We aimed to (i) explore the role of HBcrAg and pgRNA as markers of treatment eligibility in treatment naive patients, and (ii) determine any associations with tissue or immunological phenotypes in patients on nucleoside analogue (NA) treatment. Method: Serum samples (n=137) were obtained from adults with CHBatOxfordUniversityHospitals,UK,includingthoseonandoffNA therapy (n=95 and n=42 respectively), and HBeAg positive and negative (n=17 and n=120 respectively) (Oxford Research Ethics Committee A, reference 09/H0604/20). HBV DNA, Quantitative HBcrAg and HBV pgRNA were measured along with a panel of immune biomarkers. Patient metadata were recorded from the Electronic Health Record (EHR). In untreated patients, we calculated the sensitivity and specificity of previously defined HBcrAg thresholds (>5.3, >4.8 and >3.6 log10 IU/ml) to predict HBV DNA levels relevant to treatment decisions (>200, 000, >20, 000 and >2000 IU/ ml). Wecomparedthiswiththepredictive value of HBeAg status. For those on treatment, we examined the relationship between HBcrAg, pgRNA, ALT, anda panelof tenhost immunologicalmarkerstoreflect liver inflammation and immune phenotype. Results: (i) In the untreated population, HBcrAg ≥5.3 log10 IU/ml was a highly sensitive and specific predictor of HBV DNA >200 000 IU/ml (both 100%). However HBcrAg performed poorly at lower thresholds (e.g. HBcrAg ≥4.8 log10 IU/ml had a sensitivity and specificity of 67% and 98% for predicting HBV VL >20 000IU/ml). HBcrAg was marginally better at predicting both HBV DNA of >200 000 IU/ml and>20 000IU/mlthanHBeAg(HBeAgsens/spec=100%and 97%for HBVDNA>200 000IU/mland62%and 96%forVL>20 000IU/ml).In the untreated population with HBV DNA <200 000, the correlation between HBV DNA and HBcrAg is lost, demonstrating a poor correlation between peripheral DNA levels and hepatic reservoir. (ii) In the treated population, mean treatment duration was 24 months at the time of sample collection (range 0–84 months, IQR= 31.5). Median serum HBV DNA levels were below the limit of quantification but HBcrAg and pgRNA were persistent (median 3.6 S1060 log10 IU/ml, and 1.7 log10U/ml respectively). Neither of these biomarkers correlated with ALT (p=0.4 and 0.8 respectively), or with any of a panel of host immunological biomarkers (p>0.2 in all cases). Figure: HBV DNA and HBcrAg levels with HBcrAg thresholds (red dashed lines) and HBV DNA levels used for treatment eligibility (blue dashed lines). Blue shading represents those with HBcrAg >5.3 log10U/ml and HBV DNA>200 000IU/ml. Conclusion: In settings where HBV DNA quantification is not available, HBcrAg could support treatment decisions, particularly in pregnancy to prevent MTCT (based on WHO thresholds). However, HBcrAg tests are not yet widelyavailable, have cost implications, and may be only marginally better than existing HBeAg testing. In patients on NA therapy, HBcrAg or pgRNA represent quantifiable serum markers of the HBV cccDNA pool and transcriptional activity years after HBV DNA is undetectable in serum. This offers new opportunities for disease stratification. Further longitudinal work in larger cohorts will help determine the use of HBcrAg and pgRNA in prediction of long-term disease outcomes.
Original languageEnglish
Article numberdoi.org/10.1016/S0168-8278(23)03159-8
Pages (from-to)S1060
JournalJournal of Hepatology
Volume78
Issue numberS1
DOIs
Publication statusPublished - Jun 2023
Externally publishedYes

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