Novel viral markers and the prediction of off‐treatment relapse in chronic hepatitis B patients: A systematic review

Abstract

Background and Aim Hepatitis B core‐related antigen (HBcrAg) and hepatitis B virus RNA (HBV RNA) are novel markers that reflect intrahepatic cccDNA and could be useful in the prediction of relapse after nucleos(t)ide analogues (NA) discontinuation. The aim of the study is to perform a systematic review on this issue. Methods Medline/Pubmed database was searched using text terms related to HBcrAg, RNA, NAs, discontinuation, and relapse. Included studies were those that enrolled adult patients who had been on NAs for more than 6 months with available information on end‐of‐treatment (EOT) HBcrAg and/or HBV RNA and relapse rates. Results Sixteen studies were included. Virological and clinical relapse rates ranged from 11% to 100% and 11% to 73%, respectively. Low or undetectable EOT HBcrAg levels were associated with low off‐treatment relapse rates in most studies with area under the receiver operating characteristic curve (AUROC) of 0.69–0.70 for predicting virological relapse (VR) and 0.61–0.77 for predicting clinical relapse (CR). Undetectable EOT HBV RNA was associated with a lower risk of off‐treatment relapse with AUROC of 0.65–0.76 for predicting VR and 0.66–0.73 for predicting CR. Combined EOT HBcrAg and HBV RNA performed better in predicting off‐treatment relapse than either test alone with AUROC of 0.816–0.846 for predicting CR. None of the patients with double‐negative HBV RNA and HBcrAg developed CR. Conclusion Combining HBcrAg with HBV RNA or HBsAg improved the discriminating abilities in the prediction of off‐treatment relapse of each test. Patients with double‐negative HBcrAg and HBV RNA at EOT had low risks of relapse and could be considered for NA discontinuation.

Clinical Utility of SCALE-B to Predict Hepatitis B Virus Relapse, Hepatitis B Surface Antigen Loss After Antiviral Cessation in Asian Patients After 2-Year Follow-up

“…However, the efficiency of using qHBsAg as the sole predictor of HBsAg clearance was not confirmed in a subgroup of Asian patients ( 30 ). Serum HBcrAg, another biomarker encompassed hepatitis B core antigen, HBeAg, and p22 protein, is also a potential marker that reflects the intrahepatic transcription of cccDNA ( 10 , 14 , 15 , 31 ). TDF, when used as a final antiviral before treatment discontinuation, was reported to be associated with higher and shorter time to relapse than in entecavir users ( 32 , 33 ).…”

“…Serum HBV RNA is an emerging marker used for predicting the phase of HBV infection in patients with CHB and is useful for identifying patients who could benefit from discontinuation of therapy ( 31 ). However, there have been some discrepancies in the value of this marker, which are likely due to the different cut-off levels used, the heterogeneity of measurement techniques, and the various subtypes of RNA ( 20 ).…”

“…In addition, the use of combined biomarkers could improve patient evaluation; a recent systematic review demonstrated that the combination of novel biomarkers performed better than the use of a single biomarker ( 31 ). For example, using serum HBcrAg and HBV RNA together had a greater accuracy in predicting off-therapy relapse than using serum HBV RNA alone ( 9 , 19 , 31 , 34 ).…”

“…In addition, the use of combined biomarkers could improve patient evaluation; a recent systematic review demonstrated that the combination of novel biomarkers performed better than the use of a single biomarker ( 31 ). For example, using serum HBcrAg and HBV RNA together had a greater accuracy in predicting off-therapy relapse than using serum HBV RNA alone ( 9 , 19 , 31 , 34 ). These results are consistent with our findings that the SCALE-B, which involves a combination of several predictive variables, is a better predictive method for off-therapy relapse than HBV RNA, which provides no additional benefit to the SCALE-B score.…”

Translational Strategies to Eliminate Chronic Hepatitis B in Children: Prophylaxis and Management in East Asian Countries

“…Serum HBV RNA levels correlate more strongly with intrahepatic cccDNA levels than HBV DNA load and HBsAg levels before and after treatment (58). The levels of hepatitis B core-related antigen (HBcrAg) and HBV RNA are also useful in predicting offtreatment relapse (59).…”