Incidence and factors associated with functional cure (HBsAg seroclearance) during ETV or TDF therapy for chronic hepatitis B (CHB): an international real-world study with long-term follow-up

Abstract

Background: HBsAg seroclearance is often regarded as the therapeutic endpoint for oral nucleos(t)ide analog (NA) therapy for chronic hepatitis B (CHB), but long-term data from patients treated with entecavir (ETV) or tenofovir disoproxil fumarate (TDF) are limited. We aimed to clarify the incidence and determinants of HBsAg seroclearance during ETV or TDF treatment. Methods: This retrospective cohort study included previously treatment-naïve adult CHB patients without baseline malignancy from 13 centers from eight countries or regions in the U.S., Europe, and Asia Pacific who initiated on ETV or TDF monotherapy. Patients were observed for HBsAg seroclearance for up to 10 years, until death, loss to follow-up, or March 01, 2020, whichever came first. We calculated the incidence and explored the determinants of HBsAg seroclearance using competing risk analysis adjusted for mortality. Results: The analysis included 5,188 patients with a median age of 50 years (68.6% male, 85.7% Asian, 27.5% HBeAg+, and 23.7% cirrhosis). During a median follow-up of 4.9 (IQR, 3.0--8.1) years, HBsAg clearance occurred in 67 patients yielding a 10-year cumulative incidence of 2.19% (95% CI, 1.62--2.89%) and an average annual rate of 0.24% (95% 0.19--0.31%) without significant change over time (Table). On multivariable competing risk regression analysis, the baseline factors independently associated with HBsAg seroclearance included low level of serum HBV DNA <2,000 IU/mL (adjusted sub-distribution HR [aSHR], 2.84; 95% CI, 1.65--4.87; P<0.001), acute flare with alanine aminotransferase (ALT) >200 U/L (aSHR, 3.17; 95% CI, 1.76--5.72; P<0.001), hyperbilirubinemia >2mg/dL (aSHR, 3.65; 95% CI, 1.87--7.14; P<0.001), and presence of fatty liver on ultrasound examination (aSHR, 2.17; 95% CI, 1.24--3.80; P=0.006). Conclusion: HBsAg seroclearance rarely occurs in CHB patients treated with ETV or TDF with an annual incidence of 0.24% - a much lower rate than prior reported rates for untreated patients of usually about 1%, and was associated with low level viremia, ALT flare, hyperbilirubinemia, and fatty liver. These findings indicate that HBsAg seroclearance is a remote or even unrealistic endpoint of the current antiviral strategy, while providing a realistic reference point for future HBV cure clinical trial design.