Pauline Arends

Entecavir treatment does not eliminate the risk of hepatocellular carcinoma in chronic hepatitis B: limited role for risk scores in Caucasians

Background Hepatocellular carcinoma (HCC) risk-scores may predict HCC in Asian entecavir (ETV)-treated patients. We aimed to study risk factors and performance of risk scores during ETV treatment in an ethnically diverse Western population. Methods We studied all HBV monoinfected patients treated with ETV from 11 European referral centres within the VIRGIL Network. Results A total of 744 patients were included; 42% Caucasian, 29% Asian, 19% other, 10% unknown. At baseline, 164 patients (22%) had cirrhosis. During a median follow-up of 167 (IQR 82–212) weeks, 14 patients developed HCC of whom nine (64%) had cirrhosis at baseline. The 5-year cumulative incidence rate of HCC was 2.1% for non-cirrhotic and 10.9% for cirrhotic patients (p<0.001). HCC incidence was higher in older patients (p<0.001) and patients with lower baseline platelet counts (p=0.02). Twelve patients who developed HCC achieved virologic response (HBV DNA <80 IU/mL) before HCC. At baseline, higher CU-HCC and GAG-HCC, but not REACH-B scores were associated with development of HCC. Discriminatory performance of HCC risk scores was low, with sensitivity ranging from 18% to 73%, and c-statistics from 0.71 to 0.85. Performance was further reduced in Caucasians with c-statistics from 0.54 to 0.74. Predicted risk of HCC based on risk-scores declined during ETV therapy (all p<0.001), but predictive performances after 1 year were comparable to those at baseline. Conclusions Cumulative incidence of HCC is low in patients treated with ETV, but ETV does not eliminate the risk of HCC. Discriminatory performance of HCC risk scores was limited, particularly in Caucasians, at baseline and during therapy.

Incidence and predictors of hepatocellular carcinoma in Caucasian chronic hepatitis B patients receiving entecavir or tenofovir

BACKGROUND & AIMS The risk of hepatocellular carcinoma (HCC) in Caucasian patients with chronic hepatitis B (CHB), treated with entecavir (ETV) or tenofovir (TDF), is unclear. We evaluated the incidence and predictors of HCC and the accuracy of existing HCC risk scores in Caucasian CHB patients receiving ETV/TDF. METHODS This large, multicentre, retrospective cohort study included 1666 adult Caucasian CHB patients under ETV/TDF for 39 months. CHB without cirrhosis, compensated and decompensated cirrhosis were present in 67%, 39%, and 3% of patients, respectively. The predictability of baseline parameters and three risk scores (GAG-HCC, CU-HCC, and REACH-B), developed in Asian patients, was assessed. RESULTS The cumulative probability of HCC was 1.3%, 3.4%, and 8.7% at year-1, year-3, and year-5 after ETV/TDF onset. Older age and lower platelets were strong independent HCC predictors in the total population and in the subgroups of cirrhotic and non-cirrhotic patients, while liver disease severity was an independent HCC predictor in the total population and in the cirrhotics. GAG-HCC, CU-HCC, and REACH-B risk scores were associated with HCC development only in the univariable but not in the multivariable analyses and offered poor to modest predictability. CONCLUSIONS HCC can still develop in Caucasian CHB patients treated with ETV/TDF. Besides the well-known predictors of HCC, such as older age, male gender and more advanced liver disease, lower platelets represent an independent factor of higher HCC risk. The applicability and predictability of HCC risk scores developed in Asian patients are poor or modest in Caucasian CHB patients, for whom different risk scores are required.

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.

Serum levels of interferon-gamma-inducible protein 10 and response to peginterferon therapy in HBeAg-positive chronic hepatitis B

BACKGROUND & AIMS Serum levels of interferon-gamma inducible protein 10 (IP-10) are a marker for immune activity, and may predict response to peginterferon (PegIFN) therapy in chronic hepatitis B. METHODS IP-10 was measured at baseline and on-treatment week 12 in 210 HBeAg-positive patients treated with PegIFN for 52 weeks. Response to treatment was assessed at 6 months post-treatment and defined as HBeAg loss, combined response (HBeAg loss with HBV DNA <10,000 c/ml) or HBsAg loss. RESULTS Median baseline IP-10 levels were 158 pg/ml. Higher baseline IP-10 was associated with more HBV DNA, HBeAg and HBsAg decline from week 4 onwards, and IP-10 was higher in patients who achieved HBeAg loss (p=0.001) and combined response (p=0.052). A combination of high IP-10 (>150 pg/ml) with absence of precore (PC) and core promoter (BCP) mutants strongly predicted combined response and HBsAg loss: 48% of patients with high IP-10 and no detectable mutants achieved a combined response (p<0.001). A minimal non-significant decline from baseline was observed to week 12 (0.015 log pg/ml, p=0.52 compared to baseline), but decline was somewhat more pronounced in patients who achieved HBeAg loss (0.05 logpg/ml, versus an increase of 0.05 in patients without HBeAg loss, p=0.04). CONCLUSIONS Higher pre-treatment IP-10 levels are associated with an increased probability of HBeAg loss after PegIFN therapy. A combination of high baseline IP-10 and absence of PC and BCP mutants identified patients with the highest probability of combined response and HBsAg loss. There appears little use for on-treatment quantification of IP-10 for prediction of response to PegIFN.

Repeated Measurements of Hepatitis B Surface Antigen Identify Carriers of Inactive HBV During Long-term Follow-up

BACKGROUND & AIMS Measurements of hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA might help to identify carriers of inactive HBV. We assessed the performance of repeated measurements of HBsAg over a median time period of 8 years. METHODS We performed a retrospective study of 292 HBe antigen-negative patients with chronic HBV infection, normal levels of alanine aminotransferase (ALT), levels of HBV DNA <20,000 IU/mL, and no cirrhosis who visited the outpatient clinics at 8 tertiary care centers in Europe, Asia, and Australia from 1990 through 2011. Patients were determined to be carriers of inactive HBV (level of HBV DNA <2000 IU/mL and serum levels of ALT that remained normal) or to have HBV activity (level of HBV DNA fluctuating >2000 IU/mL and/or abnormal levels of ALT) after each year of follow-up. Patients were followed for a median time of 8 years (range, 4-9 years). Dynamic regression analysis was used to study changes in level of HBsAg and HBV phase and to update the risk of HBV activity. RESULTS One year after study enrollment, 189 patients (65%) had inactive HBV and 103 patients (35%) had HBV activity. Based on dynamic analysis, the probability that a patient would have HBV at any following year differed according to level of HBsAg; odds were 97% for patients with initial level of HBsAg <100 IU/mL, 85% for patients with initial levels 100-1000 IU/mL, and 76% for patients with initial levels >1000 IU/mL (P < .001). Having inactive virus for any 2 consecutive years predicted having inactive virus in any third year. However, 15% of patients with level of HBsAg >100 IU/mL had HBV activity in the third year. The combination of HBsAg level <100 IU/mL and HBV DNA level <2000 IU/mL identified patients whose virus remained inactive for the entire follow-up period, with 98% specificity and a positive predictive value of 97%, for all HBV genotypes. Patients with HBV activity who had levels of HBV DNA <5000 IU/mL and decreases in HBsAg of 0.5 log IU/mL or more for 1 year had a high probability of becoming carriers of inactive HBV in the next year. CONCLUSIONS In a retrospective, dynamic analysis of almost 300 patients with chronic HBV infection, we found that levels of HBsAg <100 IU/mL identify patients with inactive virus with a high level of specificity. HBsAg levels should therefore be used to define phases of HBV infection in HBe antigen-negative patients.

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.

P1075 PAGE-B: RISK SCORE FOR HEPATOCELLULAR CARCINOMA (HCC) DEVELOPMENT IN CAUCASIAN CHRONIC HEPATITIS B (CHB) PATIENTS RECEIVING ENTECAVIR (ETV) OR TENOFOVIR (TDF)

Area under receiver operating characteristics curve (AUC) showed that HBsAg 360 IU/mL at 6 month was predictive for its clearances at EOT (PPV 86.2%, specificity 83.5%), and 10 IU/mL at 12 months was a guide to prolonged treatment (PPV 85.7%, specificity 91.4%). During follow-up, 14 of 50 patients with HBsAg clearance (28.0%) had HBsAg reversion. Among them, only three patients developed mild hepatitis, whereas convalescent status was stable in most of them. Conclusions: On-treatment HBsAg monitoring could be used to tailor the regimen and improve the HBsAg response. HBsAg seroreversion may occur even in patients with pegIFNa2a-induced HBsAg clearance.

Loss of intrahepatic HBsAg expression predicts sustained response to peginterferon and is reflected by pronounced serum HBsAg decline

There is a lack of knowledge regarding the effect of peginterferon (PEG‐IFN) on the expression of intrahepatic hepatitis B core and surface antigen (HBcAg and HBsAg) in chronic hepatitis B (CHB) and its relation with response to therapy. Fifty‐two HBeAg‐positive and 67 HBeAg‐negative CHB patients with paired liver biopsies taken at baseline and after 1 year of PEG‐IFN therapy were studied. After PEG‐IFN therapy, HBeAg‐negative patients showed a significant reduction in both intrahepatic HBcAg (P = 0.04) and HBsAg expression (P < 0.001). In contrast, a reduction in intrahepatic HBcAg expression was not observed in HBeAg‐positive patients, while a trend in reduction of intrahepatic HBsAg staining was found (P = 0.09). Post‐treatment, 7 (13%) HBeAg‐positive and 9 (14%) HBeAg‐negative patients had no expression of intrahepatic HBsAg. Patients without any intrahepatic HBsAg expression post‐treatment were more likely to achieve a combined response (HBeAg loss with hepatitis B virus (HBV) DNA <2000 IU/mL for HBeAg ‐positive and HBV DNA <2000 IU/mL and normal alanine aminotransferase for HBeAg‐negative CHB): 71% vs 5% for HBeAg‐positive (P < 0.001) and 60% vs 16% for HBeAg‐negative patients (P = 0.004), respectively. Moreover, a more profound decline of serum HBsAg was observed in patients with absence of intrahepatic HBsAg staining (3.1 vs 0.4 log IU/mL, P < 0.001 and 1.7 vs 0.4 log IU/mL, P = 0.005 for HBeAg‐positive and HBeAg‐negative CHB, respectively). In conclusion, PEG‐IFN reduces expression of intrahepatic HBsAg. Loss of HBsAg as assessed by immunohistochemistry from the liver predicts a sustained response and is reflected in a pronounced serum HBsAg decline.

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).