HBV RNA as a Biomarker for Safe Antiviral Discontinuation: A Prospective Study of Nucleos(t)ide Analogue Withdrawal

Abstract Introduction Withdrawal of nucleos(t)ide analog (NA) therapy is associated with hepatitis B surface antigen (HBsAg) loss and sustained, off-therapy partial cure (normal ALT [≤30 U/L males, ≤20 U/L females) with HBV DNA <2000 IU/mL) but should be offered only to those most likely to benefit. HBVRNA may be useful for risk stratification. Methods The Hepatitis B Research Network Immune-Active Trial prospectively evaluated treatment with tenofovir (TDF) for 192 weeks ± peginterferon-α (PegIFN) for initial 24 weeks followed by protocolized withdrawal of TDF amongst eligible participants (NCT01369212). HBV RNA was evaluated as predictor of ALT flares and sustained partial cure (HBV DNA<2000 IU/mL) 48 weeks after TDF withdrawal. Results Of 93 participants discontinuing TDF (52 in TDF+PegIFN and 41 in TDF alone), 52 (55.9%) had unquantifiable HBVRNA at end-of-treatment. ALT flares (>5xULN) at 48 weeks off-therapy occurred in 33.3%, with pre-treatment age (≥35 years) and quantifiable HBV RNA at end-of-treatment, the best predictors (AUROC 0.74 and 0.85, training and test set) of ALT flare. A total of 26 (28.3%) had sustained partial cure; 3 (11.5%) with ALT flare. Non-quantifiable HBVRNA and qHBsAg <100 IU/mL at end-of-treatment were the best predictors of sustained partial cure (AUROC 0.84 and 0.93, training and test set). If HBVRNA was quantifiable at end-of-treatment, the likelihood of sustained partial cure was only 3% whereas if HBV RNA was unquantifiable and qHBsAg <100 IU/mL, this likelihood was 73%. Conclusions HBVRNA is a useful biomarker in predicting likelihood of achieving sustained partial cure and safe withdrawal of NAs.