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We would like to thank Drs. Debnath and Rathi for their interest in our recent article. In our study, we used data from a multicenter multiethnic cohort to identify predictors of virologic response (VR), hepatitis B surface antigen (HBsAg) loss, and alanine aminotransferase flares after nucleo(s)tide analogue withdrawal. As also highlighted by Drs Debnath and Rathi, lower levels of hepatitis B core antigen (HBcrAg) and HBsAg were associated with favorable off-treatment outcomes (ie, higher rates of VR and HBsAg loss, and lower rates of alanine aminotransferase flares). Although the observed associations were robust in subgroup analysis, it should be appreciated that neither HBcrAg nor HBsAg levels were a perfect predictor of off-treatment outcomes; patients with low viral antigen levels had higher chances favorable outcomes, but only a limited subset of patients complied with these criteria. [...

Host and Viral Predictors of Response to Antiviral Therapy in Chronic Hepatitis B

Chronic hepatitis B (CHB) is a major cause of liver disease worldwide despite the availability of effective vaccination. There are still more than 350 million people chronically infected with the hepatitis B virus (HBV)1 and progression of HBV-related liver inflammation to cirrhosis, hepatic decompensation and hepatocellular carcinoma (HCC) is estimated to result in up to 1.2 million deaths annually

Probability of HBsAg loss after nucleo(s)tide analogue withdrawal depends on HBV genotype and viral antigen levels

HBV genotype; Viral antigenGenotipo VHB; Antígeno viralGenotip del VHB; Antigen viralBackground & Aims Nucleo(s)tide analogue (NUC) withdrawal may result in HBsAg clearance in a subset of patients. However, predictors of HBsAg loss after NUC withdrawal remain ill-defined. Methods We studied predictors of HBsAg loss in a global cohort of HBeAg-negative patients with undetectable HBV DNA who discontinued long-term NUC therapy. Patients requiring retreatment after treatment cessation were considered non-responders. Results We enrolled 1,216 patients (991 with genotype data); 98 (8.1%) achieved HBsAg loss. The probability of HBsAg loss was higher in non-Asian patients (adjusted hazard ratio [aHR] 8.26, p 100 IU/ml) and HBcrAg (100 IU/ml with detectable HBcrAg. HBsAg loss rates also varied with HBV genotype; the highest rates were observed for genotypes A and D, and none of the patients with HBV genotype E experienced HBsAg loss (p <0.001 for the overall comparison across genotypes; p <0.001 for genotypes A/D vs. genotypes B/C). HBV genotype C was independently associated with a higher probability of HBsAg loss when compared to genotype B among Asian patients (aHR 2.494; 95% CI 1.490–4.174, p = 0.001). Conclusions The probability of HBsAg loss after NUC cessation varies according to patient ethnicity, HBV genotype and end-of-treatment viral antigen levels. Patients with low HBsAg (<100 IU/ml) and/or undetectable HBcrAg levels, particularly if non-Asian or infected with HBV genotype C, appear to be the best candidates for treatment withdrawal.The CREATE study was supported by Fujirebio. No additional funding was obtained for this follow-up analysis

Liver stiffness is associated with excess mortality in the general population driven by heart failure:The Rotterdam Study

Background: Elevated liver stiffness reflects hepatic fibrosis but can also be secondary to venous congestion. We aimed to study the association between liver stiffness and mortality in the general population, stratified for heart failure and/or coronary heart disease (CHD). Methods: We analysed individuals enrolled in the ongoing prospective population-based Rotterdam Study who attended a visit between 2009–2014 that included liver stiffness measurement. Exclusion criteria for the primary analysis were incomplete data on heart failure, unreliable liver stiffness, alcohol abuse and viral hepatitis, leaving 4.153 participants (aged 67.5 ± 8.4 years, 44.2% male) for analysis with a median follow-up of 6.0 (interquartile range: 5.1–7.0) years. Secondary analysis included participants with viral hepatitis, alcohol abuse and/or unreliable measurement. The association between liver stiffness and mortality was assessed using Cox regression. Associations between heart failure, CHD, and echocardiographic characteristics and liver stiffness were quantified with linear regression. Results: Liver stiffness ≥8.0 kPa was associated with mortality (aHR: 1.37, 95%CI: 1.00–1.89). However, this was driven by participants with heart failure (aHR: 2.48, 95%CI: 1.15–5.35), since high liver stiffness was not associated with mortality in participants without heart failure and/or CHD (aHR: 1.07, 95%CI: 0.70–1.64). Results were consistent when individuals with viral hepatitis, alcohol abuse or unreliable liver stiffness measurement were not excluded. Several cardiovascular characteristics were significantly associated with higher liver stiffness, e.g. heart failure, moderate/poor diastolic dysfunction, and right atrium diameter &gt; 4.5 cm. Conclusion: In our cohort of community-dwelling elderly, high liver stiffness was associated with excess mortality, primarily explained by participants with heart failure. Moreover, heart failure and its indicators were associated with increased liver stiffness.</p

Lower pretreatment HBV DNA levels are associated with better off-treatment outcomes after nucleo(s)tide analogue withdrawal in patients with HBeAg-neegative chronic hepatitis B: A multicentre cohort study

Entecavir; HBV DNA; TenofovirEntecavir; ADN del VHB; TenofovirEntecavir; ADN del VHB; TenofovirBackground & Aims Pretreatment predictors of finite nucleo(s)tide analogue (NUC) therapy remain elusive. We studied the association between pretreatment HBV DNA levels and outcomes after therapy cessation. Methods Patients with chronic hepatitis B who were HBeAg negative at the start of NUC treatment were enrolled from sites in Asia and Europe. We studied the association between pretreatment HBV DNA levels and (1) clinical relapse (defined as HBV DNA >2,000 IU/ml + alanine aminotransferase >2 × the upper limit of normal or retreatment) and (2) HBsAg loss after NUC withdrawal. Results We enrolled 757 patients, 88% Asian, 57% treated with entecavir, with a median duration of treatment of 159 (IQR 156–262) weeks. Mean pretreatment HBV DNA levels were 5.70 (SD 1.5) log IU/ml and were low (20,000 IU/ml) in 607 (80%). The cumulative risk of clinical relapse at 144 weeks after therapy cessation was 22% among patients with pretreatment HBV DNA levels 20,000 IU/ml, whereas the cumulative probabilities of HBsAg loss were 17.5% vs. 5% (p <0.001). In multivariable analysis, pretreatment HBV DNA levels <20,000 IU/ml were independently associated with a reduced likelihood of clinical relapse (adjusted hazard ratio 0.379, p <0.001) and with an increased chance of HBsAg loss (adjusted hazard ratio 2.872, p <0.001). Conclusions Lower pretreatment HBV DNA levels are associated with a lower risk of clinical relapse and a higher chance of HBsAg loss after cessation of NUC therapy, independent of end-of-treatment viral antigen levels. Further studies are needed to confirm these findings in non-Asian populations. Impact and Implications A subgroup of patients with chronic hepatitis B may not require retreatment after stopping antiviral therapy. In this study, comprising 757 patients with chronic hepatitis B from Europe and Asia, we found that higher viral load before initiation of treatment was a risk factor for relapse after stopping treatment. Patients with a low HBV DNA level before starting antiviral therapy had the lowest risk of relapse, and a high chance of HBsAg loss, after stopping treatment. These findings can help select patients for treatment withdrawal and guide intensity of off-treatment monitoring.The CREATE study was supported by Fujirebio. Materials for HBcrAg testing were provided free of charge to several participating centres. Fujirebio had no influence on CREATE study design, data collection, data analysis, writing of the current manuscript, or the decision to submit for publication

The Role of PIVKA-II as a Predictor of Early Hepatocellular Carcinoma Recurrence-Free Survival after Liver Transplantation in a Low Alpha-Fetoprotein Population

Introduction: AFP and the RETREAT score are currently used to predict HCC recurrence after LT. However, superior discriminating models are needed for low AFP populations. The aim of this study is to investigate the predictive value of PIVKA-II on recurrence-free survival after LT in a low AFP population and microvascular invasion on explant. Methods: A retrospective cohort study including all consecutive patients transplanted for HCC between 1989 and 2019 in the Erasmus MC University Medical Center in Rotterdam, the Netherlands, was used. AFP and PIVKA-II levels were determined in serum samples collected at the time of transplantation. Data on tumor load and microvascular invasion were retrieved from patients’ records. Results: The study cohort consisted of 121 patients, with HCC recurrence in 15 patients (12.4%). The median AFP was 7.7 ng/mL (4.4–20.2), and the median PIVKA-II was 72.0 mAU/mL (41.0–213.5). Patients with low AFP (≤8 ng/mL) and PIVKA-II (≤90 mAU/mL) had a 5-year recurrence-free survival of 100% compared to 85.7% in patients with low AFP and high PIVKA-II (p = 0.026). Regardless of the AFP level, patients within the Milan criteria (based on explant pathology) with a low PIVKA-II level had a 5-year recurrence-free survival of 100% compared to patients with a high PIVKA-II level of 81.1% (p = 0.002). In patients with microvascular invasion, the AUC for PIVKA-II was slightly better than the AUC for AFP (0.775 vs. 0.687). Conclusions: The dual model of PIVKA-II ≤ 90 mAU/mL with either AFP ≤ 8 ng/mL or with patients within the Milan criteria identifies patient groups which can be exempted from HCC surveillance after LT in a low AFP population. PIVKA-II may be a better predictor for explant microvascular invasion than AFP and could play a role in future models identifying LT candidates with the highest risk for HCC recurrence.</p

The Yield of Routine Post-Operative Doppler Ultrasound to Detect Early Post-Liver Transplantation Vascular Complications

Early detection of liver transplantation (LT) vascular complications enables timely management. Our aim was to assess if routine Doppler ultrasound (rDUS) improves the detection of hepatic artery thrombosis (HAT), portal vein thrombosis (PVT) and hepatic venous outflow obstruction (HVOO). We retrospectively analysed timing and outcomes, number needed to diagnose one complication (NND) and positive predictive value (PPV) of rDUS on post-operative day (POD) 0,1 and 7 in 708 adult patients who underwent primary LT between 2010–2022. We showed that HAT developed in 7.1%, PVT in 8.2% and HVOO in 3.1% of patients. Most early complications were diagnosed on POD 0 (26.9%), 1 (17.3%) and 5 (17.3%). rDUS correctly detected 21 out of 26 vascular events during the protocol days. PPV of rDUS was 53.8%, detection rate 1.1% and NND was 90.5. Median time to diagnosis was 4 days for HAT and 47 days for PVT and 21 days for HVOO. After intervention, liver grafts were preserved in 57.1%. In conclusion, rDUS protocol helps to detect first week’s vascular events, but with low PPV and a high number of ultrasounds needed.</p

The Yield of Routine Post-Operative Doppler Ultrasound to Detect Early Post-Liver Transplantation Vascular Complications

Early detection of liver transplantation (LT) vascular complications enables timely management. Our aim was to assess if routine Doppler ultrasound (rDUS) improves the detection of hepatic artery thrombosis (HAT), portal vein thrombosis (PVT) and hepatic venous outflow obstruction (HVOO). We retrospectively analysed timing and outcomes, number needed to diagnose one complication (NND) and positive predictive value (PPV) of rDUS on post-operative day (POD) 0,1 and 7 in 708 adult patients who underwent primary LT between 2010–2022. We showed that HAT developed in 7.1%, PVT in 8.2% and HVOO in 3.1% of patients. Most early complications were diagnosed on POD 0 (26.9%), 1 (17.3%) and 5 (17.3%). rDUS correctly detected 21 out of 26 vascular events during the protocol days. PPV of rDUS was 53.8%, detection rate 1.1% and NND was 90.5. Median time to diagnosis was 4 days for HAT and 47 days for PVT and 21 days for HVOO. After intervention, liver grafts were preserved in 57.1%. In conclusion, rDUS protocol helps to detect first week’s vascular events, but with low PPV and a high number of ultrasounds needed.</p