Remote and Short-Term Prediction of Spontaneous Hepatitis B Surface Antigen Seroclearance

The recent study of Tseng et al1Tseng T.C. et al.Gastroenterology. 2023; 164: 669-679Abstract Full Text Full Text PDF Google Scholar on the kinetics of hepatitis B core-related antigen (HBcrAg) has provided a new insight into the remote prediction of spontaneous hepatitis B surface antigen (HBsAg) seroclearance. However, several points require clarification or further discussion. First, it has been well documented that spontaneous HBsAg loss invariably occurs after hepatitis B e antigen (HBeAg) seroconversion and an HBeAg-negative inactive phase of 10–15 years.2Chu C.M. et al.Antivir Ther. 2010; 15: 133-143Crossref PubMed Scopus (145) Google Scholar The findings of earlier HBcrAg decline with a time lag of 10–14 years before HBsAg seroclearance may coincide with those of spontaneous HBeAg seroconversion. Conceivably, before HBeAg seroconversion, HBeAg-positive patients are not candidates for HBsAg loss. In addition, because HBeAg is the most predominant component of HBcrAg, HBeAg-positive patients have high HBcrAg levels with a median of up to 8–9 log10 IU/mL vs 2–4.5 log10 in HBeAg-negative patients.3Adrabeda C. et al.J Hepatol. 2023; 78: 731-741Abstract Full Text Full Text PDF Scopus (0) Google Scholar Hence, including HBeAg-positive patients in the analyses with HBcrAg ≥ 5 log10 IU/mL as a reference may create bias by inadvertently inflating the impact of high HBcrAg levels on the cumulative incidence of HBsAg loss. Although the study demonstrated that HBcrAg < 10,000 IU/mL is significantly associated with HBsAg loss in HBeAg-negative patients, perhaps recalculation of Kaplan-Meier analyses restricted to HBeAg-negative patients only in Figures 1–3 would reveal different results from those of the entire cohort (including HBeAg-positive patients) and might even reach different conclusions. Second, in Table 1, the upper limit of normal for alanine aminotransferase was set at 35 U/L for males and 25 U/L for females to define the disease stage. However, it was not explained why alanine aminotransferase was categorized as <20, 20–39, and ≥40 U/L instead of less than vs more than the upper limit of normal in their analyses. Third, surprisingly, age was not a significant factor in HBeAg-negative patients with HBsAg > 1000 IU/mL. The differences may become significant in categorized comparisons using a reported cutoff age of 40 or 50.2Chu C.M. et al.Antivir Ther. 2010; 15: 133-143Crossref PubMed Scopus (145) Google Scholar Fourth, the results of the study have confirmed the authors’ earlier observation that HBsAg < 100 IU/mL is a good predictor for HBsAg loss in the next 6–10 years.4Tseng T.C. et al.Hepatology. 2012; 55: 68-76Crossref PubMed Scopus (122) Google Scholar Given that the natural course of chronic hepatitis B virus infection is a dynamic process, especially during the HBeAg-positive immune active phase, remote prediction of HBsAg loss may have limited value in clinical decisions. Two Asian studies have shown a threshold HBsAg level of 200 IU/mL plus an HBsAg decline of >0.5 log10 IU/mL in the preceding 1 year or the following 1 year showed very high negative and positive predictive values in predicting HBsAg loss within 1–3 years.5Chen Y.C. et al.Clin Gastroenterol Hepatol. 2012; 10: 297-302Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar,6Seto W.K. et al.Hepatology. 2012; 56: 812-819Crossref PubMed Scopus (82) Google Scholar Obviously, short-term prediction of HBsAg loss within a much shorter period of 1–3 years is more relevant and useful in daily clinical practice than remote prediction described in this study. In conclusion, this study supports HBcrAg as a remote predictor for HBsAg loss. However, some issues need to be clarified. In clinical settings, the sensitivity, specificity, reproducibility, and expected high market price as compared with quantitative HBsAg assay are concerns of the HBcrAg assay. This is also a limitation of the study to be discussed. Low Hepatitis B Core–Related Antigen Levels Correlate Higher Spontaneous Seroclearance of Hepatitis B Surface Antigen in Chronic Hepatitis B Patients With High Hepatitis B Surface Antigen LevelsGastroenterologyVol. 164Issue 4PreviewSeroclearance of hepatitis B surface antigen (HBsAg) indicates functional cure for hepatitis B virus (HBV) infection. Low HBsAg levels can predict HBsAg seroclearance over time. However, little is known about the association between hepatitis B core–related antigen (HBcrAg) levels and spontaneous seroclearance of HBsAg. Full-Text PDF ReplyGastroenterologyPreviewWe appreciate the comments by Hsu et al on our article, as it helps the readers better understand our data.1 To address the role of hepatitis B core-related antigen (HBcrAg) levels in hepatitis B e-antigen (HBeAg)–negative patients, we restricted our analysis to 2111 HBeAg-negative patients, and found a consistent association between lower HBcrAg levels and higher spontaneous sero-clearance rates of hepatitis B surface antigen (HBsAg) (P for trend <0.001). Moreover, when we specifically restricted the analysis to 1083 HBeAg-negative patients with HBsAg levels greater than 1000 IU/mL, we observed that HBcrAg levels <10,000 IU/mL were still associated with a higher likelihood of spontaneous HBsAg clearance compared with HBcrAg levels ≥100,000 IU/mL, with a hazard ratio of 1.92 (95% confidence interval 1.11–3.33) (Table 3 in the original paper). Full-Text PDF