Heng Chi

Reduced risk of relapse after long-term nucleos(t)ide analogue consolidation therapy for chronic hepatitis B

Before stopping nucleos(t)ide analogue (NA) treatment in chronic hepatitis B (CHB), 6–12 months of consolidation therapy is recommended.

The risk of hepatocellular carcinoma decreases after the first 5 years of entecavir or tenofovir in Caucasians with chronic hepatitis B

Whether there is a change of hepatocellular carcinoma (HCC) incidence in chronic hepatitis B patients under long‐term therapy with potent nucleos(t)ide analogues is currently unclear. We therefore assessed the HCC incidence beyond year 5 of entecavir/tenofovir (ETV/TDF) therapy and tried to determine possible factors associated with late HCC occurrence. This European, 10‐center, cohort study included 1,951 adult Caucasian chronic hepatitis B patients without HCC at baseline who received ETV/TDF for ≥1 year. Of them, 1,205 (62%) patients without HCC within the first 5 years of therapy have been followed for 5‐10 (median, 6.8) years. HCCs have been diagnosed in 101/1,951 (5.2%) patients within the first 5 years and 17/1,205 (1.4%) patients within 5‐10 years. The yearly HCC incidence rate was 1.22% within and 0.73% after the first 5 years (P = 0.050). The yearly HCC incidence rate did not differ within and after the first 5 years in patients without cirrhosis (0.49% versus 0.47%, P = 0.931), but it significantly declined in patients with cirrhosis (3.22% versus 1.57%, P = 0.039). All HCCs beyond year 5 developed in patients older than 50 years at ETV/TDF onset. Older age, lower platelets at baseline and year 5, and liver stiffness ≥12 kPa at year 5 were independently associated with more frequent HCC development beyond year 5 in multivariable analysis. No patient with low Platelets, Age, Gender‐Hepatitis B score at baseline or year 5 developed HCC. Conclusion: The HCC risk decreases beyond year 5 of ETV/TDF therapy in Caucasian chronic hepatitis B patients, particularly in those with compensated cirrhosis; older age (especially ≥50 years), lower platelets, and liver stiffness ≥12 kPa at year 5 represent the main risk factors for late HCC development. (Hepatology 2017;66:1444–1453).

Hepatitis A related acute liver failure by consumption of contaminated food

We present a patient with no medical history admitted for jaundice and dark coloured urine. Further investigations revealed hepatitis A related acute liver failure while the patient had no travel history, nor contact with infected individuals. After admission, the patient deteriorated fulfilling the Kings College criteria for acute liver failure. Two days after admission, he underwent liver transplantation and recovered. Careful investigation identified imported semi-dried tomatoes as the source of the hepatitis A infection. This patient was part of a foodborne hepatitis A outbreak in the Netherlands in 2010 affecting 13 patients. Virus sequence analysis of our patients virus showed a strain commonly found in Turkey. Hepatitis A related acute liver failure is rare, but is associated with a poor prognosis. In developed countries, the incidence of hepatitis A is low, but foodborne outbreaks are emerging. Further, we review the literature on recent foodborne hepatitis A outbreaks in developed countries, hepatitis A related acute liver failure, and hepatitis A vaccine.

Pegylated Interferon Alfa-2b Add-on Treatment in Hepatitis B Virus Envelope Antigen-Positive Chronic Hepatitis B Patients Treated with Nucleos(t)ide Analogue: A Randomized, Controlled Trial (PEGON).

Background We studied whether 48 weeks of pegylated interferon alfa-2b (peginterferon) add-on therapy increases serological response in hepatitis B virus (HBV) envelope antigen (HBeAg)-positive patients receiving nucleos(t)ide analogue (NA) therapy, compared with continued NA monotherapy. Methods This randomized trial included HBeAg-positive patients with compensated liver disease who were treated with entecavir/tenofovir for >12 months and had an HBV DNA load of <2000 IU/mL. Patients were randomly assigned in a 1:1 ratio to 48 weeks of peginterferon add-on therapy (n = 39) or continued NA monotherapy (n = 38). Response (defined as HBeAg seroconversion with an HBV DNA load of <200 IU/mL) was assessed at week 48, with responders discontinuing NA therapy at week 72. Results The primary end point (response at week 96) was achieved in 18% of patients who were assigned peginterferon add-on therapy versus 8% of patients assigned NA monotherapy (P = .31). Among 58 interferon-naive patients, add-on therapy led to a greater frequency of HBeAg seroconversion (30% vs 7%; P = .034) and response (26% vs 7%; P = .068) at week 96, compared with monotherapy. Among 8 responders at week 48 who discontinued NA therapy at week 72, 6 patients (75%) maintained a response until week 96 (4 of 6 [67%] in the add-on therapy group vs 2 of 2 [100%] in the monotherapy group; P = 1.00). Adverse events were mainly related to peginterferon. Conclusion The primary end point was negative, but peginterferon add-on therapy appeared to result in a greater frequency of HBeAg seroconversion, compared with NA monotherapy, in interferon-naive patients receiving NA therapy. Clinical Trials Registration NCT01532843.

Off-Treatment Hepatitis B Virus (HBV) DNA Levels and the Prediction of Relapse After Discontinuation of Nucleos(t)ide Analogue Therapy in Patients With Chronic Hepatitis B: A Prospective Stop Study

Background The optimal management remains unknown after nucleos(t)ide analogue (NA) discontinuation in patients with chronic hepatitis B (CHB). This prospective study investigated the role of off-treatment viral kinetics in predicting relapse after discontinuation of NA therapy. Methods A total of 82 noncirrhotic Asian patients with CHB who discontinued NA therapy according to international guidelines were prospectively followed. Patients with a hepatitis B virus (HBV) DNA level of >2000 IU/mL and an alanine aminotransferase (ALT) level of >2 times the upper limit of normal (clinical relapse) were retreated. Results Sixty patients were HBV envelope antigen (HBeAg) positive at the start of treatment, and 22 were HBeAg negative. Clinical relapse developed in 28 patients (2-year rates, 31% among HBeAg-positive patients and 53% among HBeAg-negative patients). Age of ≤35 years (hazard ratio [HR], 0.37; P = .026) and end-of-treatment HBsAg level of ≤200 IU/mL (HR, 0.39; P = .078) were independently associated with lower relapse rates. A high risk of biochemical relapse (defined as an ALT level of >2 times the upper limit of normal) was observed if the HBV DNA level was >200000 IU/mL when the level was initially elevated, compared with HBV DNA levels of >2000 to ≤200000 IU/mL (HR, 8.42; P < .001). The risk of biochemical relapse was also high in patients with persistent elevation in the HBV DNA level (confirmed to be >2000 IU/mL within 3 months), compared with the group with transient elevation (HR, 6.87; P < .001). Conclusions After NA discontinuation, a lower relapse rate was observed in younger patients and in those with low end-of-treatment HBsAg levels. The level and persistence of off-treatment elevated HBV DNA levels were useful in the prediction of a subsequent biochemical relapse and may thus be used to guide off-treatment management.

Flares during long-term entecavir therapy in chronic hepatitis B.

The incidence and consequences of flares during first‐line nucleos(t)ide analogue therapy are largely unknown. We aimed to investigate the incidence and outcome of alanine aminotransferase (ALT) flares during long‐term entecavir (ETV) in chronic hepatitis B (CHB).

Multiple biopsy passes and the risk of complications of percutaneous liver biopsy.

Background and aim To minimize the sample variability of liver biopsy, the tissue length should be at least 25 mm. Consequently, more than one biopsy pass is needed with cutting biopsy needles. We aimed to investigate the risk factors of biopsy-related complication, including the number of biopsy passes. Methods All consecutive liver biopsies performed between 2005 and 2014 were included. Biopsies were ultrasound assisted and performed with cutting biopsy needles. A complication was an event where the patient visited a healthcare provider because of biopsy-related complaints. Complications followed by hospitalization 2 or more days or intervention were considered severe. Results In total, 1806 liver biopsies were analyzed. Overall, 102 (5.6%) complications were observed, of which 31 (1.7%) were severe. One (0.06%) patient died. Common complications were pain (n=75/102; 74%) and bleeding (n=34/102; 33%). Two biopsy passes were not associated with an increased risk of complications compared with one biopsy pass [odds ratio (OR): 1.59; 95% confidence interval (CI): 0.83–3.04; P=0.16], whereas three or more biopsy passes increased this risk compared with one (OR: 2.97; 95% CI: 1.38–6.42; P=0.005) or two biopsy passes (OR: 1.87; 95% CI: 1.10–3.19; P=0.021). The risk of severe complications was not influenced by the number of biopsy passes (P>0.24). Hepatic malignancy (OR: 3.21; 95% CI: 1.18–8.73; P=0.022) and international normalized ratio 1.4 or more (OR: 7.03; 95% CI: 2.74–18.08; P<0.001) were risk factors of severe complications. Conclusion Severe complication rate and mortality were low. Performing multiple biopsy passes was not associated with severe complications, whereas hepatic malignancy or elevated international normalized ratio were associated with an increased risk.

Eight-year survival in chronic hepatitis B patients under long-term entecavir or tenofovir therapy is similar to the general population

BACKGROUND & AIMS The effects of long-term antiviral therapy on survival have not been adequately assessed in chronic hepatitis B (CHB). In this 10-centre, ongoing cohort study, we evaluated the probability of survival and factors affecting survival in Caucasian CHB patients who received long-term entecavir/tenofovir therapy. METHODS We included 1,951 adult Caucasians with CHB, with or without compensated cirrhosis and without hepatocellular carcinoma (HCC) at baseline, who received entecavir/tenofovir for ≥12 months (median, six years). Kaplan-Meier estimates of cumulative survival over time were obtained. Standardized mortality ratios (SMRs) were calculated by comparing death rates with those in the Human Mortality Database. RESULTS The one-, five-, and eight-year cumulative probabilities were 99.7, 95.9, and 94.1% for overall survival, 99.9, 98.3, and 97.4% for liver-related survival, and 99.9, 97.8, and 95.8% for transplantation-free liver-related survival, respectively. Overall mortality was independently associated with older age and HCC development, liver-related mortality was associated with HCC development only, and transplantation-free liver-related mortality was independently associated with HCC development and lower platelet levels at baseline. Baseline cirrhosis was not independently associated with any type of mortality. Compared with the general population, in all CHB patients mortality was not significantly different (SMR 0.82), whereas it was lower in patients without HCC regardless of baseline cirrhosis (SMR 0.58) and was higher in patients who developed HCC (SMR 3.09). CONCLUSION Caucasian patients with CHB and compensated liver disease who receive long-term entecavir/tenofovir therapy have excellent overall and liver-related eight-year survival, which is similar to that of the general population. HCC is the main factor affecting their overall mortality, and is the only factor affecting their liver-related mortality. LAY SUMMARY Caucasian patients with chronic hepatitis B with or without compensated cirrhosis who receive long-term entecavir or tenofovir therapy have excellent overall eight-year survival, which is similar to that of the general population. Hepatocellular carcinoma is the main factor affecting their overall mortality, and is the only factor affecting liver-related mortality in this setting.

Durability of Response After Hepatitis B Surface Antigen Seroclearance During Nucleos(t)ide Analogue Treatment in a Multiethnic Cohort of Chronic Hepatitis B Patients: Results After Treatment Cessation.

In 70 chronic hepatitis B patients with hepatitis B surface antigen seroclearance during nucleos(t)ide analogue therapy, response was sustained in all 54 patients who discontinued treatment. Clinically significant relapses as indicated by high hepatitis B virus DNA and ALT levels were not observed. Anti-HBs positivity may not be required to ensure sustained off-treatment response.

Younger age and language barriers are associated with nonadherence to clinical follow-up in hepatitis B treatment

We investigated the incidence and predictors of non-adherence towards clinic visits in chronic hepatitis B (CHB) patients on entecavir or tenofovir treatment. This was a retrospective study of CHB patients treated for at least 3 months in a tertiary referral hospital in The Netherlands. Lack of attendance in clinic visits was defined as a missed follow-up visit without notice. 338 patients (48% Caucasian, 37% Asian) were followed for a median of 3.5 years. During 1283 person-years, 183 scheduled follow-up visits were missed in 101 patients resulting in 0.14 missed visit per person-year. The cumulative rates of first missed follow-up visit were 14%, 28%, and 38% at year 1, 3, and 5, respectively. Reappearance time from a non-attended visit until the next visit was 1.6 months. Ten patients were lost to follow-up (3% at year 5). After a missed visit, 3 patients developed high HBV DNA and/or ALT level when they reappeared at the next visit. Younger age (Hazard ratio [HR] 0.97, p=0.003) and language barrier (HR 1.80, p=0.011) were associated with non-attendance in a multivariable model. Language barrier was reported in 82 patients of whom the majority originated from China (n=45/82; 55%) and Turkey (n=19/82; 23%). Non-adherence to clinical follow-up was infrequent in this multiethnic cohort of treated CHB patients. A small amount of patients developed clinically relevant HBV DNA or ALT elevations after a missed visit. Younger patients and patients with language barrier had higher rates of follow-up non-adherence. This article is protected by copyright. All rights reserved.