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

Abstract

Background: Withdrawal of nucleos(t)ide analogue therapy is associated with hepatitis B surface antigen (HBsAg) loss and sustained off-therapy partial cure (normal alanine aminotransferase [ALT] ≤30 U/L for males and ≤20 U/L for females with hepatitis B virus [HBV] DNA <2000 IU/mL) but should be offered only to those most likely to benefit. HBV RNA may be useful for risk stratification.

Methods: The Hepatitis B Research Network Immune-Active Trial prospectively evaluated treatment with tenofovir disoproxil fumarate (TDF) for 192 weeks ± peginterferon alfa-2a for the initial 24 weeks, followed by protocolized withdrawal of TDF among eligible participants (ClinicalTrials.gov NCT01369212). HBV RNA was evaluated as a predictor of ALT flares and sustained partial cure (HBV DNA <2000 IU/mL) 48 weeks after TDF withdrawal.

Results: Of 93 participants discontinuing TDF (n = 52, TDF + peginterferon alfa-2a; n = 41, TDF alone), 52 (55.9%) had unquantifiable HBV RNA at end of treatment. ALT flares >5 times the upper limit of normal at 48 weeks off therapy occurred in 33.3%, with pretreatment age (≥35 years) and quantifiable HBV RNA at end of treatment the best predictors (area under the receiver operating characteristic curves, 0.74 and 0.85 for training and test sets, respectively). A total of 26 (28.3%) had sustained partial cure, 3 (11.5%) with ALT flare. Nonquantifiable HBV RNA and quantitative HBsAg <100 IU/mL at end of treatment were the best predictors of sustained partial cure (area under the receiver operating characteristic curves, 0.84 and 0.93 for training and test sets). If HBV RNA was quantifiable at end of treatment, the likelihood of sustained partial cure was only 3%, whereas if HBV RNA was unquantifiable and quantitative HBsAg was <100 IU/mL, this likelihood was 73%.

Conclusions: HBV RNA is a useful biomarker in predicting likelihood of achieving sustained partial cure and safe withdrawal of nucleos(t)ide analogues.

Keywords: ALT flare; HBsAg loss; functional cure; partial cure; peginterferon.