Clinical Outcome Event Adjudication in a 10-Year Prospective Study of Nucleos(t)ide Analogue Therapy for Chronic Hepatitis B

Abstract

Background and Aims: In the REALM (Randomized, Observational Study of Entecavir to Assess Long-Term Outcomes Associated with Nucleoside/Nucleotide Monotherapy for Patients with Chronic HBV Infection) study, 12,378 patients with chronic hepatitis B virus (HBV) infection received up to 10 years of randomized therapy with entecavir or another HBV nucleos(t)ide analogue. Monitored clinical outcome events (COEs) included malignant neoplasms, HBV disease progression events, and deaths. An external event adjudication committee (EAC) was convened to provide real-time review of reported COEs to optimize data quality, and minimize potential adverse effects of the large cohort, interdisciplinary outcome assessments, geographic scope, and long duration. Methods: The EAC comprised an international group of hepatologists and oncologists with expertise in diagnosis of targeted COEs. The EAC reviewed and adjudicated COEs according to prospectively defined diagnostic criteria captured in the EAC charter. Operational processes, including data collection and query procedures, were implemented to optimize efficiency of data recovery to maximize capture of adjudicated COEs, the primary study outcome measure. Results: A total of 1724 COEs were reported and 1465 of these events were adjudicated by the EAC as reported by the investigators (85.0% overall concordance). Concordance by COE type varied: deaths, 99.6%; hepatocellular carcinoma (HCC), 83.3%; non-HCC malignancies, 88.0%; non-HCC HBV disease progression, 68.2%. Reasons for lack of concordance were most commonly lack of adequate supporting data to support an adjudicated diagnosis or evidence that the event pre-dated the study. Conclusions: The REALM EAC performed a critical role in ensuring data quality and consistency; EAC performance was facilitated by well-defined diagnostic criteria, effective data capture, and efficient operational processes. Trial registration: ClinicalTrials.gov NCT00388674.

What Should Be Done to Re-evaluate Cessation of Nucleos(t)ide Analog Therapy for Chronic Hepatitis B Infection?

“…Mono-therapy using NUCs with high genetic barriers against resistance, such as ETV, TDF, and TAF can effectively suppress HBV replication to an undetectable level within 1 year [12–22] . However, there is a limited rate of HBeAg seroconversion and is extremely difficult to achieve HBsAg loss and hence to render a clinical cure in CHB patients (Table 2).…”

“…However, there is a limited rate of HBeAg seroconversion and is extremely difficult to achieve HBsAg loss and hence to render a clinical cure in CHB patients (Table 2). [12–22] …”

“…Nucleos(t)ide analogs or pegylatedinterferon monotherapy is difficult to achieve functional cure Mono-therapy using NUCs with high genetic barriers against resistance, such as ETV, TDF, and TAF can effectively suppress HBV replication to an undetectable level within 1 year. [12][13][14][15][16][17][18][19][20][21][22] However, there is a limited rate of HBeAg seroconversion and is extremely difficult to achieve HBsAg loss and hence to render a clinical cure in CHB patients (Table 2). [12][13][14][15][16][17][18][19][20][21][22] For HBeAg-positive CHB patients, the rate of achieving serum HBV DNA negativity, with 48 to 52 weeks of ETV or TDF therapy, were 67% and 76%, respectively.…”

Development a novel nomogram model for predicting significant hepatic histological changes in chronic hepatitis B virus carriers

“…1 Anti-HBV treatment has been proved to effectively reduce the risk of HBV related liver cirrhosis and HCC. [2][3][4] According to current HBV practice guidelines, patients who do not receive antiviral therapy should not develop serious liverrelated complications. However, a considerable majority of chronic hepati B (CHB) patients fail to receive antiviral therapy which may lead to disease progression, mainly because they cannot meet the existing recommendations from the major international CHB treatment guidelines.…”

“…Chronic hepatitis B virus (HBV) infection remains a predominant cause of HBV‐related complications, including liver cirrhosis and hepatocellular carcinoma (HCC) 1 . Anti‐HBV treatment has been proved to effectively reduce the risk of HBV related liver cirrhosis and HCC 2‐4 . According to current HBV practice guidelines, patients who do not receive antiviral therapy should not develop serious liver‐related complications.…”