Durability of Spontaneous and Treatment-Related Loss of Hepatitis B s Antigen

Abstract

Background & aims: Clearance of hepatitis B surface antigen (HBsAg) from serum is the most desirable end point and a proposed definition of functional cure for hepatitis B virus (HBV) infection. However, little is known about the long-term durability of HBsAg loss, and there is controversy over whether the development of antibodies against HBsAg (anti-HBs) is required for maintenance. We aimed to assess the durability of spontaneous or treatment-related (interferon or nucleos(t)ide analogue [NA]) loss of HBsAg.

Methods: We performed a retrospective study of patients with chronic HBV infection followed up at the National Institutes of Health from February 1980 through November 2017. We identified those with HBsAg loss, confirmed on 2 visits at least 24 weeks apart. Patients with hepatitis C virus, hepatitis D virus, human immunodeficiency virus, or human T lymphocyte virus co-infection or HBsAg loss after liver transplantation were excluded. Patients were assigned to the following groups: spontaneous clearance (cleared HBsAg without ever receiving treatment or those who received treatment with a NA or interferon and discontinued therapy >5 years before HBsAg loss), interferon-treated (cleared HBsAg either during treatment or ≤5 years after stopping interferon), and NA-treated (cleared HBsAg either during treatment or ≤5 years after stopping NA).

Results: Among the 787 HBsAg-positive patients, 89 achieved HBsAg loss; 65 of 89 had confirmed HBsAg loss, which was spontaneous in 19 of the patients (29%), after interferon in 22 (34%), and after NA in 24 (37%). Of the 65 patients with confirmed loss of HBsAg, 62 patients (95%) remained HBsAg negative after a mean time of 9.6 years from the first negative HBsAg test result. HBsAg seroreversion occurred in 3 of the 46 treated patients (7%) (1 interferon and 2 NA), 1 of whom was positive for anti-HBs. At the time of HBsAg loss, 33 of 65 (51%) were anti-HBs positive. At the last follow-up evaluation, anti-HBs was detectable in 50 of the 62 patients (81%) assessed. The rate of development of anti-HBs was proportionally higher among interferon-treated patients (19 of 21; 90%) than NA-treated patients (17 of 22; 77%) or patients with spontaneous loss of HBsAg (14 of 19; 74%).

Conclusions: In a retrospective study of 787 HBsAg-positive patients, loss of HBsAg (either spontaneous or after treatment) was confirmed in 8% and was durable. Seroconversion to anti-HBs increased over time and appeared to be more frequent after interferon treatment. HBsAg loss is therefore a robust end point for functional cure.

Keywords: CHB; Outcome; Seroconversion; Vaccination.

Figure 1:. Study Consort Diagram

Participants included in the analysis. HIV-human immunodeficiency virus, HTLV1-Human T-cell leukemia virus type 1, HCV-hepatitis C virus, HDV-hepatitis D virus

Figure 2a:

Prior Treatment History and Course of Patients with Spontaneous HBsAg Loss. *Patient received adefovir for 5 years and then discontinued treatment 7 years prior to initiating care at NIH. ^‡Patient received entecavir for 3 years and then discontinued therapy before initiating care at NIH.

Figure 2b:

Prior Treatment History and Course of Patients with Interferon-related HBsAg loss.

Figure 2c:

Prior Treatment History and Course of Patients with Nucleos(t)ide analogue-related HBsAg loss. Prior NA treatment indicated by yellow bar, an asterisk and a double cross; prior interferon treatment indicated by purple bar. Green bar indicates period of HBsAg positivity since initial visit. Black bar indicates time of HBsAg loss. Red bar indicates duration of follow-up after HBsAg loss.

Figure 3a:

Kaplan-Meier Analysis of Durability of HBsAg loss

Figure 3b:

Cumulative Incidence of Development of anti-HBs

Figure 4a:

Proportion with anti-HBs at time of initial HBsAg loss by mode of HBsAg loss.

Figure 4b:

Proportion with anti-HBs at time of last follow up visit by mode of HBsAg loss. Magenta bar spontaneous HBsAg loss; orange bar interferon-related HBsAg loss; green bar nucleos(t)ide-related HBsAg loss.