Durability of Hepatitis B Surface Antigen Loss With Nucleotide Analogue and Peginterferon Therapy in Patients With Chronic Hepatitis B

Abstract

In patients with chronic hepatitis B (CHB), loss of hepatitis B surface antigen (HBsAg) is considered a functional cure. However, HBsAg loss is uncommon with existing therapies, and predictive factors associated with HBsAg seroreversion are unknown. Using pooled data from three phase 3 clinical trials of patients with CHB treated with nucleos(t)ide analogue (NUC) monotherapy or peginterferon (Peg-IFN) ± NUC combination therapy, we conducted a retrospective analysis to characterize patients who achieved sustained HBsAg loss, the predictors of HBsAg seroreversion, and the impact of hepatitis B surface antibody (anti-HBs) seroconversion on durability of HBsAg loss. In these three international trials, 1,381 adults with CHB received either NUC monotherapy for up to 10 years or Peg-IFN-containing regimens for up to 1 year. A total of 55 patients had confirmed HBsAg loss, defined as two or more consecutive negative-qualitative HBsAg results, with a minimum of one repeat result after the end of treatment. Throughout a median of 96 (quartile [Q]1, Q3, 46, 135) weeks follow-up after HBsAg loss, HBsAg loss was durable in 82% (n = 45) of patients, with 10 patients experiencing HBsAg seroreversion. Anti-HBs seroconversion was observed during follow-up in 78% of patients who lost HBsAg and in 60% of those who subsequently seroreverted. In analyzing predictors of HBsAg seroreversion, study treatment was significant, yet anti-HBs seroconversion and treatment duration after initial HBsAg loss were not. Risk of HBsAg seroreversion was observed to be lower if HBsAg loss was sustained through the off-treatment week 24 visit (8/10 seroreversions occurred by posttreatment week 24). Conclusion: HBsAg loss after NUC or Peg-IFN-containing regimens was durable in 82% of patients with CHB. Anti-HBs seroconversion and treatment duration after initial HBsAg loss were not significantly associated with durability of HBsAg loss.

Figure 1

Flow chart showing patient selection and outcomes. *HBsAg seroreversion occurred during treatment in 3 patients and off treatment in 2 patients; all remained HBsAg positive for the remainder of the study. Abbreviation: FU, follow‐up.

Figure 2

Durability of HBsAg loss in patients with and without anti‐HBs seroconversion. Bars represent 95% confidence intervals. White text within bars represent n/N.

Figure 3

Timing of HBsAg loss, anti‐HBs seroconversion, and HBsAg seroreversion. Each line is an individual patient. The length of the line indicates treatment duration in the study, and the symbols indicate the key events. Patients are sorted from top to bottom in order by HBsAg seroreversion occurrence, treatment category, on‐ or off‐treatment HBsAg loss, HBsAg seroconversion occurrence, and off‐treatment HBsAg loss duration.

Figure 4

Change in plasma HBV DNA (log₁₀ IU/mL), serum ALT (log₂ U/L), and serum HBsAg levels in patients with HBsAg seroreversion. Quantitative changes in HBV DNA (red circles), ALT (green circles), and HBsAg (blue circles) levels over time in the 10 patients with HBsAg seroreversion.

Figure 5

KM plots of estimated probability of durable HBsAg loss to last study visit and to week 72. Patients treated with Peg‐IFN had a shorter duration of follow‐up, up to week 72 (insert) after HBsAg loss. (A) All 55 patients with confirmed HBsAg loss and all 10 patients with HBsAg seroreversion. (B) Modified KM estimate, including all 55 patients with confirmed HBsAg loss and 8 patients with confirmed HBsAg seroreversion.

Figure 6

Forest plot showing predictors of HBsAg seroreversion. Consolidation of treatment refers to the duration of treatment from time of initial HBsAg loss. Abbreviation: ADV, adefovir.