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

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.