How Durable Is Functional Cure (Hepatitis B Surface Antigen Loss) in Patients With Chronic Hepatitis B Treated With Current Antivirals?

The achievement of hepatitis B surface antigen (HBsAg) loss and its durability off treatment are of paramount importance for current and future anti-hepatitis B virus (HBV) strategies. Because HBsAg loss is a rare event, multicenter studies and pooled analyses may be instrumental, as demonstrated by Lok et al.(1) in this issue of Hepatology Communications. Among 1,381 patients with chronic hepatitis B (CHB) treated with either tenofovir disoproxil fumarate (TDF) monotherapy for up to 10 years or pegylated interferon (PEG-IFN)-containing regimens for up to 1 year and enrolled in three international trials, 55 (3.9%) had confirmed HBsAg loss. Of these 55 patients, 29 received TDF monotherapy and 26 were treated with PEG-IFN with or without TDF; 45 (82%) had confirmed and sustained HBsAg loss and 10 seroreverted to HBsAg positivity during a median follow-up period of 96 (46-135) weeks after first HBsAg loss. The risk of HBsAg seroreversion was lower if HBsAg loss was sustained through off treatment. Overall, antibody to hepatitis B surface antigen (anti-HBs) seroconversion was observed in 43 (78%) patients who achieved HBsAg loss, with similar rates in patients treated with nucleos(t)ide (NUC) and PEG-IFN (79% vs. 77%, respectively). This study is important for several reasons. First, in a well-characterized population followed for many years, the rate of drug-induced HBsAg loss is indeed a rare event (<5%). Second, the study describes carefully the durability of HBsAg loss and the probability of anti-HBs seroconversion over time. Third, the combination of TDF and PEG-IFN increased the rates of HBsAg loss compared to TDF monotherapy. As far as the probability of HBsAg during antiviral treatment for HBV is concerned, most studies agree that this is a rare event that is possibly related to duration of NUC therapy, baseline HBsAg levels, disease severity, and phases of the natural history of HBV, among other predictors. These disappointingly low rates of HBsAg loss relate mainly to the mechanism of action of NUC therapy, which does not directly interfere with viral antigen production or secretion. One might ask why this endpoint, HBsAg loss, is so Abbreviations: anti-HBs, antibody to hepatitis B surface antigen; CHB, chronic hepatitis B; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; IFN , interferon; NAP, nucleic acid polymer; NUC, nucleos(t)ide; PEG-IFN, pegylated interferon; TDF, tenofovir disoproxyl fumarate.