Stephanos J. Hadziyannis

Background and Aims: Scarce data exist on the effect of nucleos(t)ide analogue (NA) discontinuation on hepatocellular carcinoma (HCC) risk in HBeAg‐negative chronic hepatitis B (CHBe−). Therefore, we assessed whether HCC risk is increased in non‐cirrhotic CHBe− patients who discontinue compared to those remaining on NAs.Methods: This cohort study included 650 consecutive non‐cirrhotic Caucasian or Asian patients with CHBe− without a history of HCC who discontinued NAs after a median of 5 or 3 years (cases, n = 325; Caucasians: 143, Asians: 182) or remained on NA therapy beyond 5 or 3 years respectively (controls, n = 325; Caucasians: 223, Asians: 102). Propensity score (PS) 1:1 matching was applied to adjust for patients' origin, age and sex.Results: During a median follow‐up of 44 months, HCC developed in 7/325 cases and 9/325 controls or 7/245 PS‐matched cases and 7/245 PS‐matched controls with 5‐year cumulative HCC incidence of 5.1% and 4.9% respectively (log‐rank, P = .836). No difference in 5‐year HCC risk was observed between cases and controls of Caucasian (3.0% vs 4.8%; log‐rank, P = .510) or Asian origin (1.3% vs 2.2%; log‐rank, P = .873). In both cases and controls, HCC incidence was independently associated with age and PAGE‐B score. In cases alone, HCC development after NA discontinuation was associated only with pretreatment platelet counts and PAGE‐B score, but not with any type of relapse or HBsAg loss.Conclusions: Our findings suggest that discontinuation of effective long‐term NA therapy in non‐cirrhotic CHBe− patients are not associated with increased HCC risk, which is not affected by post‐NA relapses and/or HBsAg loss.

Introduction: Long-term, even indefinite treatment with nucleos(t)ide analogs (NAs) is the current first-line therapy for patients with chronic hepatitis B (CHB), regardless of its histological stage. Guidelines and recommendations on duration and endpoints of NA therapy in CHB are not identical and change over time. Areas covered: The authors review NA discontinuation approaches and views with an emphasis on HBeAg-negative patients based on published studies relevant to the topic, stressing on whether or not the optimal endpoint of HBsAg loss is practically achievable. Expert opinion: Discontinuation of NA therapy in HBeAg-negative noncirrhotic patients has to be considered after long-term effective treatment with controlled liver disease activity, undetectable viremia, and significant decline in serum HBsAg titers. Close post-treatment monitoring is required for early intervention in cases of severe clinical relapse. Immediate retreatment hampers the favorable outcome of HBsAg clearance (functional cure) and should be avoided in transient ALT flares. Predictors of such relapses are still under investigation and include viral and patient factors. For HBeAg-positive noncirrhotic patients, there is wide acceptance of the endpoint of HBeAg seroconversion, after a long consolidation period.

Hepatocellular carcinoma (HCC) is a major health problem worldwide, representing one of the leading causes of death. Chronic hepatitis B virus (HBV) infection (CHB) is the most important etiologic factor of this tumor, accounting for the development of more than 50% of the cases in the world. Primary prevention of HCC is possible by hepatitis B vaccination conferring protection from HBV infection. However, according to the World Health Organization Hepatitis B Fact sheet N° 204 (update of July 2014) globally there exists a large pool of > 240 million people chronically infected with HBV who are at risk for development of HCC. These individuals represent a target population for secondary prevention both of cirrhosis and of HCC. Since ongoing HBV replication in CHB is linked with the progression of the underlying liver disease to cirrhosis as well as with the development of HCC, effective antiviral treatment in CHB has also been evaluated in terms of secondary prevention of HCC. Currently, most patients with active CHB are subjected to long term treatment with the first line nucleos(t)ide analogues entecavir and tenofovir. These compounds are of high antiviral potency and have a high barrier to HBV resistance compared to lamivudine, adefovir dipivoxil and even telbivudine. Many studies have shown that patients under antiviral treatment, especially those in virological remission, develop less frequently HCC compared to the untreated ones. However, the risk for development of HCC cannot be eliminated. Therefore, surveillance for the development of HCC of patients with chronic hepatitis B must be lifelong or until a time in the future when new treatments will be able to completely eradicate HBV from the liver particularly in the early stages of CHB infection. In this context, the aim of this review is to outline the magnitude of the risk for development of HCC among patients with CHB, in the various phases of the infection and in relation to virus, host and environmental factors as evaluated in the world literature. Moreover, the benefits of antiviral treatment of CHB with nucleos/tide analogs, which have changed the natural history of the disease and have reduced but not eliminated the risk of HCC are also reviewed.

JCTH,Journal of Clinical and Translational Hepatology

Serum HBsAg levels have been quantified extensively in recent years with simple completely automated assays in the various phases of the natural course of chronic HBV infection, have been compared with cccDNA in the liver, with various markers of HBV replication and have been correlated with several viral, host and environmental variables. Low HBsAg levels in inactive carriers predict a spontaneous HbsAg loss. Quantification of HBsAg in serum at baseline and its decline under interferon-alfa based regimens, both in HBeAg-positive and HBeAg-negative CHB, provides important information on the prediction of sustained post-treatment outcomes and on subsequent HBsAg clearance. The value of HBsAg quantification in the monitoring of long term nucleos(t)ide analogue treatment of CHB and in the prediction of sustained response remains unclear. In this review, the most recent data regarding the overall clinical utility of HBsAg measurement in HBeAg-positive and -negative CHB and in their treatment, is critically presented.