Serum levels of hepatitis B core antibodies and hepatitis B core-related antigen at the time of nucleos(t)ide analog cessation and risk of severe flares in patients with chronic hepatitis B

Background: In the nucleos(t)ide analog (NA)-control arm of the REEF-2 study (NCT04129554), virologic relapse (confirmed increase in HBV DNA >2000 IU/mL) and biochemical flare (ALT increases ≥3× upper limit of normal) were frequently observed after stopping NA treatment. We characterized the posttreatment virologic relapses and biochemical flares and assessed their association with end-of-treatment (EOT) HBV serum markers. Methods: In REEF-2, a randomized-controlled study, virologically suppressed HBeAg-negative patients stopped treatment at week 48, followed by 48 weeks of follow-up. EOT HBV RNA, hepatitis B core-related antigen, and quantitative anti-hepatitis B core (HBc) IgG levels were assessed in 41/45 NA-control arm patients; their association with off-treatment response was evaluated. Results: A similar proportion of patients with EOT HBV RNA or hepatitis B core-related antigen detectable and target not detectable had virologic relapse or ALT flares (p>0.05). A higher frequency of severe virologic relapse (peak HBV DNA >100,000 IU/mL) and/or severe biochemical flares (peak ALT ≥10× upper limit of normal) was observed in patients with EOT detectable hepatitis B core-related antigen levels, HBsAg <1000 IU/mL, and/or anti-HBc IgG titers <300 IU/mL, respectively (p<0.05). None of the 11 patients with EOT anti-HBc titers ≥300 IU/mL had severe virologic or biochemical flare off treatment (100% positive predictive value and 48% negative predictive value). Conclusions: In this prospective study of patients who stopped NA, anti-HBc levels ≥300 IU/mL were associated with a low risk of developing virologic relapse and severe biochemical flares. Future research should confirm a potential protective effect of high anti-HBc IgG levels.