Author information

¹Division of GI and Liver Diseases, University of Southern California, Los Angeles, California, USA.

²Division of Gastroenterology and Hepatology, Virginia Commonwealth University, Richmond, Virginia, USA.

³Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA.

⁴Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. Bethesda, Maryland, USA.

⁵Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.

⁶Infectious Disease Research, Abbott Diagnostics, Abbott Park, Illinois, USA.

⁷Department of Biostatistics and Computational biology, University of Rochester, Rochester, New York, USA.

⁸Department of Biostatistics, University of Pittsburgh, Pittsburgh, Philadelphia, USA.

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.