In chronic hepatitis B (CHB), an indeterminate phase exists outside the typical predefined phases. Our study investigates this indeterminate phase's natural history and prognosis, focusing on antiviral treatment outcomes.

We conducted a retrospective cohort study to compare the risk of transitioning to immune active phase between inactive and indeterminate CHB and the incidence of hepatocellular carcinoma (HCC) and cirrhosis between untreated patients with indeterminate CHB (at baseline and throughout follow-up) and those who received treatment, following standard AASLD 2018 guidance.

The risk of transitioning to the immune active phase over 3, 5, and 10 years was 6.3%, 8.9%, and 14.2%, respectively, for inactive phase patients (n = 104). For HBeAg-negative indeterminate phase patients (n = 194), the risk was significantly higher at 23.0%, 31.9%, and 38.2%, and for HBeAg-positive indeterminate phase patients (n = 140), it was 40.4%, 52.0%, and 55.0% (p < 0.001). Inverse probability of treatment weighting (IPTW) was utilized to balance the groups of treated and untreated indeterminate patients. Following IPTW adjustment, the Kaplan-Meier curve analysis indicates that the risk of HCC and cirrhosis among untreated patients (n = 294) is higher than that among treated patients (n = 76), (p = 0.015 and 0.007, respectively). In the multivariable analysis, antiviral therapy remained an independent predictor of a reduced risk of HCC (aHR 0.128, 95% CI 0.031-0.522, p = 0.005) and cirrhosis (aHR 0.148, 95% CI 0.044-0.496, p = 0.002).

The indeterminate phase patients had a high-risk transition to active phase, and antiviral therapy can reduce the incidence of developing HCC and cirrhosis.

Liver stiffness measurements (LSMs) are promising for monitoring disease progression or regression. We assessed the prognostic significance of dynamic changes in LSM over time on liver-related events (LREs) and death in patients with chronic hepatitis B (CHB) and compensated advanced chronic liver disease (cACLD).

This retrospective study included 1272 patients with CHB and cACLD who underwent at least two measurements, including LSM and fibrosis score based on four factors (FIB-4). ΔLSM was defined as [(follow-up LSM - baseline LSM)/baseline LSM × 100]. We recorded LREs and all-cause mortality during a median follow-up time of 46 months. Hazard ratios (HRs) and confidence intervals (CIs) for outcomes were calculated using Cox regression.

Baseline FIB-4, baseline LSM, ΔFIB-4, ΔLSM, and ΔLSM/year were independently and simultaneously associated with LREs (adjusted HR, 1.04, 95% CI, 1.00-1.07; 1.02, 95% CI, 1.01-1.03; 1.06, 95% CI, 1.03-1.09; 1.96, 95% CI, 1.63-2.35, 1.02, 95% CI, 1.01-1.04, respectively). The baseline LSM combined with the ΔLSM achieved the highest Harrell's C (0.751), integrated AUC (0.776), and time-dependent AUC (0.737) for LREs. Using baseline LSM and ΔLSM, we proposed a risk stratification method to improve clinical applications. The risk proposed stratification based on LSM performed well in terms of prognosis: low risk (n = 390; reference), intermediate risk (n = 446; HR = 3.38), high risk (n = 272; HR = 5.64), and extremely high risk (n = 164; HR = 11.11).

Baseline and repeated noninvasive tests measurement allow risk stratification of patients with CHB and cACLD. Combining baseline and dynamic changes in the LSM improves prognostic prediction.

This study is to explore the proportion of significant liver histopathology in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B virus (HBV)-infected patients with normal alanine aminotransferase (ALT) and investigate noninvasive indicators for predicting significant liver histopathology. A total of 201 HBeAg-negative chronic HBV-infected patients with normal ALT who underwent liver biopsy were involved in this study. Significant liver histological changes were defined as necroinflammation grade ≥2 (G ≥ 2) and/or fibrosis stage ≥2 (S ≥ 2). The results showed that 42.3% (85/201) and 45.8% (92/201) of the HBeAg-negative patients with normal ALT have significant liver necroinflammation (G ≥ 2) and fibrosis (S ≥ 2), respectively. High normal ALT (>22 U/L), high level of serum HBV DNA (>3.42 log IU/mL), and low level of prealbumin (PA) (<170 mg/L) were independent predictors for significant liver necroinflammation, and the predictive value of the combined indicators was 0.750 (P < 0.001), while high normal ALT (>24 U/L) and high level of FIB-4 (>1.53) were independent predictors for significant liver fibrosis, and the predictive value of the combined indicators was 0.740 (P < 0.001). In conclusion, more than 40% of HBeAg-negative patients with normal ALT have significant liver histopathology and require immediate antiviral treatment. ALT, PA, HBV DNA, and FIB-4 can independently predict significant liver inflammation and fibrosis for HBeAg-negative patients with normal ALT. Lowering the treatment threshold of ALT may benefit the HBeAg-negative chronic HBV-infected patients.

Hepatitis B e antigen (HBeAg)-negative chronic hepatitis B virus (HBV)-infected patients with normal alanine aminotransferase (ALT) were supposed to have a low risk of progression to cirrhosis or hepatocellular carcinoma, and it was recommended to regularly follow up or undergo liver biopsy to assess liver histopathology according to the major international guidelines. However, this study indicates that a considerable number of HBeAg-negative chronic HBV-infected patients with normal ALT have significant liver histopathology and require immediate antiviral treatment. Besides, several clinical commonly used noninvasive indicators were found that can be used to predict significant liver histopathology; thereby liver biopsy might be avoided for HBeAg-negative chronic HBV-infected patients with normal ALT.

The present letter to the editor is related to the review with the title "Past, present, and future of long-term treatment for hepatitis B virus." Chronic hepatitis B (CHB) represents an important and pressing public health concern. Timely identification and effective antiviral therapy hold the potential to reduce liver-related mortality attributable to chronic infection with hepatitis B virus (HBV) substantially. However, the current global treatment rates for CHB remain conspicuously low, with the excessively stringent treatment criteria advocated by national CHB guidelines being a contributing factor to these low rates. Nevertheless, recent strides in comprehending this malady and the emergence of novel antiviral agents prompt the imperative re-evaluation of treatment standards to extend the sphere of potential beneficiaries. An impending need arises for a novel paradigm for the classification of patients with CHB, the expansion of antiviral treatment eligibility for HBV-infected individuals, and even the streamlining of the diagnostic process for CHB to amplify cost-effectiveness and augment survival prospects.