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.

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).

Validation of noninvasive methods to predict the presence of gastroesophageal varices in a cohort of patients with compensated advanced chronic liver disease.

BACKGROUND AND AIM: The aim was to validate noninvasive methods to predict the presence of gastroesophageal varices (GEV) in patients with suspected compensated advanced chronic liver disease. METHODS: We retrospectively reviewed clinical and radiological data collected prospectively between September 2013 and September 2015. We reviewed 442 consecutive patients with suspected compensated advanced chronic liver disease measured by transient elastography (TE) and a gastroscopy. We evaluated platelets, spleen diameter, TE, liver stiffness × spleen size/platelets (LSPS), variceal risk index (VRI), Baveno VI strategy, and Augustin algorithm. RESULTS: One hundred sixty-one out of 442 patients were included. Patients with GEV were compared with patients without GEV and showed statistically significant differences in platelet count (117 SD 51 vs 149 SD 62; P = 0.02), spleen diameter (13.0 SD 1.9 vs 11.5 SD 2; P = 0.003), and TE (28 SD 15 vs 19 SD 10; P = 0.001). Single methods (platelet count and TE) diagnosed correctly 51% and 71.4% of patients. Combined methods (LSPS, VRI, Baveno VI, and Augustin algorithm) diagnosed correctly 78%, 83.6%, 45.3%, and 57.1% of patients. Patients with GEV misdiagnosed: platelets 5/161 (3.1%), TE 6/161 (3.7%), LSPS 16/159 (10%), VRI 18/159 (11.3%), Baveno VI 3/161 (1.8%), and Augustin algorithm 6/161 (3.7%). Rate of unnecessary gastroscopies: platelets 46%, TE 25%, LSPS 13%, VRI 6%, Baveno VI 53%, and Augustin algorithm 39.1%. CONCLUSIONS: A significant number of patients were classified correctly using TE, LSPS, and VRI; however, LSPS and VRI had unacceptable rates of misdiagnoses. TE is the best noninvasive single method and the Baveno VI strategy the best combined method.

PAGE-B predicts the risk of developing hepatocellular carcinoma in Caucasians with chronic hepatitis B on 5-year antiviral therapy.

BACKGROUND & AIMS: Risk scores for hepatocellular carcinoma (HCC) developed in Asians offer poor-moderate predictability in Caucasian patients with chronic hepatitis B (CHB). This nine center cohort study aimed to develop and validate an accurate HCC risk score in Caucasian CHB patients treated with the current oral antivirals, entecavir/tenofovir. METHODS: We included 1815 adult Caucasians with CHB and no HCC at baseline who received entecavir/tenofovir for ⩾12 months. Using data from eight centers (derivation dataset, n=1325), a HCC risk score was developed based on multivariable Cox models and points system for simplification. Harrell's c-index was used as discrimination, bootstrap for internal validation and the data from the 9(th) and largest center (validation dataset, n=490) for external validation. RESULTS: The 5-year cumulative HCC incidence rates were 5.7% and 8.4% in the derivation and validation dataset, respectively. In the derivation dataset, age, gender, platelets and cirrhosis were independently associated with HCC. The PAGE-B score was developed based on age, gender and platelets (c-index=0.82, 0.81 after bootstrap validation). The addition of cirrhosis did not substantially improve the discrimination (c-index=0.84). The predictability of PAGE-B score was similar (c-index=0.82) in the validation dataset. Patients with PAGE-B ⩽9, 10-17, ⩾18 had 5-year cumulative HCC incidence rates of 0%, 3%, 17% in the derivation and 0%, 4%, 16% in the validation dataset. CONCLUSION: PAGE-B, which is based only on baseline patients' age, gender and platelets, represents a simple and reliable score for prediction of the 5-year HCC risk in Caucasian CHB patients under entecavir/tenofovir.

[Impact of the incorporation of a nurse in an inflammatory bowel disease unit]. / Impacto de la incorporación de la enfermera a una unidad de enfermedad inflamatoria intestinal.

INTRODUCTION: Multidisciplinary units are needed because of the growing complexity and volume of patients with inflammatory bowel disease (IBD). OBJECTIVES: To evaluate the healthcare, economic and research impact of incorporating a nurse into the IBD unit of the Puerta de Hierro Majadahonda University Hospital. METHODS: We prospectively recorded the activity carried out by the nurse of the IBD unit from March 2010 to December 2014. RESULTS: During this period, healthcare demand progressively increased, with 1,558 patients being attended by our unit. The healthcare provided by the nurse included 5,293 electronic mails and 678 telephone calls. We estimated that this activity represented a saving of 3,504 in-person medical consultations and 852 accident and emergency department visits. Other activities consisted of monitoring treatments with biological and non-biological agents (8,371 laboratory tests), extraction of 342 blood samples, follow-up of 1047 diagnostic tests and consultations with other medical specialties, health education in self-administration of drugs in 114 patients, the performance of 158 granulocyte apheresis procedures, and participation in 25 research projects. CONCLUSION: The incorporation of a specialised nurse in an IBD unit had major economic, healthcare and research benefits.

Safety and efficacy of triple therapy with peginterferon, ribavirin and boceprevir within an early access programme in Spanish patients with hepatitis C genotype 1 with severe fibrosis: SVRw12 analysis.

BACKGROUND & AIMS: The addition of protease inhibitors (PIs) changed the hepatitis C virus (HCV) treatment standards and improved sustained viral response (SVR) rates in patients with genotype 1 HCV infection. METHODS: Prospective, multicentre, national registry that includes naïve and treatment-experienced patients with HCV genotype 1 infection, who had bridging fibrosis or cirrhosis and were treated with triple therapy (peginterferon alfa-2a or alfa-2b, ribavirin and boceprevir) as compassionate use, and in accordance with the Summary of Product Characteristics. RESULTS: Most of the patients (68.2%) were male, with a mean age of 53 years, 75% (n = 128) had HCV 1b genotype and baseline viral load of 6.2 log. According to prior treatment, 20% of patients were treatment-naïve and 80% had received prior treatment. Approximately 36.5% of patients (n = 62) reported at least one serious adverse events (SAEs) (total SAEs = 103). The most common SAEs were neutropenia (57.6%), anaemia (47.6%) and grade 3 thrombopenia (25.9%). Patients with albumin <3.5 g/dl and bilirubin >2 mg/dl had an increased relative risk (greater than one-fold) for SAEs, including infections and hepatic decompensation. In the intent-to-treat analysis (n = 170), the overall percentage of patients with SVRw12 was 46.5%. In patients with 1 log decrease at week 4 (lead-in phase), the overall SVRw12 rate was 67.0%. In the patients initiating triple therapy with boceprevir (n = 139), the global response rate was 56.4%. In a multivariate analysis, an increased probability of achieving SVR was associated with response to prior treatment (relapsers), >1 log decrease in viral load in the lead-in phase and baseline albumin >3.5 g/dl. CONCLUSIONS: Triple therapy in patients with severe fibrosis/cirrhosis is associated with a higher rate of SAE and a lower rate in comparison with patients with mild disease. However, for patients with intact liver function, it could be considered as a treatment option, when other alternatives would not be available.

Peginterferon alpha-2a and ribavirin in patients with hepatitis C virus genotype 1 infection with persistently normal alanine aminotransferase levels.

BACKGROUND AND AIM: To evaluate the efficacy and safety of peginterferon α-2a plus ribavirin at standard doses in patients with hepatitis C virus (HVC) genotype 1 infection with persistently normal alanine aminotransferase (ALT) levels. METHODS: Patients aged 18 to 65 years were included in this observational, prospective study if they had evidence of a HCV genotype 1 infection. The serum HCV RNA concentration was determined at baseline and week 12. A qualitative HCV RNA test was performed at baseline and at weeks 48 and 72. Liver function tests were performed at each study visit. The primary efficacy measure was the sustained virological response in the intention-to-treat population. Logistic regression analyses were also performed to explore predictors of virological response. RESULTS: A sustained virological response was observed in 100 of the 175 patients (57%). An early virological response and end-of-treatment response were seen in 159 patients (91%) and 133 patients (76%), respectively. Thirty-seven of the 122 evaluable patients for this outcome (30%) showed a rapid virological response. A higher viral load was a significant predictor for a lack of rapid virological response and lack of sustained virological response. There were not any unexpected safety or tolerability findings. CONCLUSIONS: Our study suggests that the efficacy of the combination of peginterferon α-2a and ribavirin in patients with HCV genotype 1 infection and normal ALT levels is at least similar to that reported in patients with elevated ALT levels.

Spleen Transient Elastography and Damping Index Identify a Subgroup of Patients Without an Acute or Chronic Response to Beta-Blockers.

Background and Aims: Monitoring of acute or chronic response to beta-blockers in patients with liver cirrhosis is based on the measurement of the HVPG. Our aim was to evaluate the response to beta-blockers with non-invasive techniques. Patients and Methods: This is a prospective observational study. Consecutive patients with an indication of primary or secondary prophylaxis of variceal bleeding who did not meet exclusion criteria were included. Acute response and chronic response were evaluated. Baseline and after acute and chronic response hepatosplenic measurements of TE and ARFI were obtained. Contrast-enhanced Doppler ultrasound was performed before and after acute and chronic responses. Results: From June 2015 to May 2018, 55 patients (14 with exclusion criteria) were included. We analyzed 41 patients, mean age 57 (SD: 8), 82.9% men, alcohol 43.9%, children A/B/C 78%/17.1%/4.9%, and 87.8% on primary prophylaxis. In all, the acute response was performed and was positive in 68.3% (CI 95: 55-85%). The chronic response was performed in 30 (73.2%) and was positive in 36.7% (CI 95: 18-55%). Basal measurements significantly related to acute response were spleen TE [responders 58.4 (SD: 23.0) KPa vs. non-responders 75 (SD: 0) KPa; p = 0.02] and damping index [non-responders 0.96 (0.8) vs. responders 0.44 (0.4), p = 0.01], and with chronic response, the spleen TE [responders 58.1 (SD: 21.4) KPa vs. non-responders 73.2 (SD: 5.5) KPa; p = 0.02], and damping index [non-chronic responders 0.8 (0.7) vs. chronic responders 0.4 (0.4), p = 0.04]. A spleen TE ≥ 74 KPa had a high sensitivity of 100% and specificity of 60% and a high NPV100% for predicting poor acute response to beta-blockers. The damping index > 0.6 showed moderate sensitivity of 67% and specificity of 69% with a high NPV of 82% for predicting poor acute response to beta-blockers. The combination of both measurements for predicting poor acute response to beta-blockers had an AUC of 0.8 (CI 95: 0.5-0.9). A spleen TE ≥ 74 KPa had a high sensitivity of 87% and specificity of 71% with a high NPV of 71% for predicting poor chronic response to beta-blockers. A damping index > 0.6 had moderate sensitivity of 60%, specificity of 82%, and NPV of 56% for predicting poor chronic response to beta-blockers. The combination of both measurements for predicting poor chronic response to beta-blockers had an AUC of 0.8 (CI 95: 0.7-0.9). Conclusion: Spleen TE and damping index can identify a subgroup of patients with poor acute or chronic response to beta-blockers.

Successful Continuation of HCV Treatment After Liver Transplantation.

BACKGROUND: Guidelines recommend that patients with hepatitis C virus (HCV)-related liver disease be treated for HCV before liver transplant (LT) to eliminate the virus before surgery. However, the unpredictability of donor organ availability may limit treatment duration. Interruption of HCV treatment with resumption post-LT is 1 potential solution which has not been investigated widely. METHODS: Patients from 5 clinical centers included in the large, national, noninterventional Hepa-C registry who started treatment with direct-acting antiviral agents while awaiting LT were identified retrospectively and followed up prospectively. Fifteen patients who had treatment interruptions around LT were identified. RESULTS: The majority of patients (12/15) received interferon-free regimens, most commonly sofosbuvir + daclatasvir (8/12), for a total of 24 weeks (13/15). Treatment was discontinued temporarily for a median of 5 (range, 2-33) days. Fourteen patients completing 12 weeks of follow-up achieved a sustained virological response. One patient who died before week 12 posttreatment achieved a response at posttreatment week 4. Treatment was generally well tolerated. Serious adverse events were recorded in 2 of 15 patients (anaemia in 1 patient; pneumonia in 1 patient); all arose after LT. CONCLUSIONS: Resumption of direct-acting antiviral agent therapy after a temporary interruption around LT was highly effective, achieving sustained virological response in all patients who completed 12 weeks of posttreatment follow-up. Treatment was generally well tolerated pretransplantation and posttransplantation, with a low rate of serious adverse events. Such a strategy may offer an important new approach to the treatment of patients awaiting LT which may be assessed in future studies.

Timing of Thiopurine or Anti-TNF Initiation Is Associated with the Risk of Major Abdominal Surgery in Crohn's Disease: A Retrospective Cohort Study.

INTRODUCTION: Early stages of Crohn's disease [CD] are predominantly inflammatory and early treatment could be useful to change the natural history of CD. We aimed to evaluate the impact of early treatment in our cohort of CD patients. METHODS: We retrospectively reviewed clinical records of all CD patients at our centre who have received immunomodulators. Time from diagnosis to first CD-related major abdominal surgery or end of follow-up was considered. Dates of diagnosis, of starting immunomodulators (thiopurines / anti-tumour necrosis factor [TNF]), and of the first CD-related surgery when appropriate were collected. RESULTS: Of 422 patients who received thiopurines, 189 operated patients started thiopurines after a median of 117 months (interquartile range [IQR] 44-196) since diagnosis; non-operated patients, after a median of 30 months [IQR 6-128], p < 0,005. Odds ratio [OR] for surgery was 1.006 (95% confidence interval [CI]1.004-1008) for each month of delay in starting thiopurines. Among 272 patients who received anti-TNFs, 137 operated patients started anti-TNFs after a median of 166 months [IQR 90-233] since diagnosis; non-operated patients after a median of 59 months [IQR 14-162]; p < 0,005. OR for surgery was 1.008 [95% CI 1.005-1.010] for each month of delay in starting anti-TNFs. Among 467 patients who received thiopurines and/or anti-TNF, 210 operated patients started any immunomodulator after a median of 120 months [IQR 48-197] since diagnosis and non-operated patients after a median of 30 months [IQR 6-126], p < 0,005. OR for surgery was 1.008 [95% CI 1.005-1.010] for each month of delay in starting immunomodulators. CONCLUSIONS: In our experience, time between diagnosis and thiopurine or anti-TNF initiation was associated with the risk of major abdominal surgery in Crohn's disease.

Aplastic anemia and severe pancytopenia during treatment with peg-interferon, ribavirin and telaprevir for chronic hepatitis C.

Telaprevir and Boceprevir are the first direct acting antivirals approved for chronic hepatitis C in combination with peg-interferon alfa and ribavirin. Pancytopenia due to myelotoxicity caused by these drugs may occur, but severe hematological abnormalities or aplastic anemia (AA) have not been described. We collected all cases of severe pancytopenia observed during triple therapy with telaprevir in four Spanish centers since approval of the drug in 2011. Among 142 cirrhotic patients receiving treatment, 7 cases of severe pancytopenia (5%) were identified and three were consistent with the diagnosis of AA. Mean age was 59 years, five patients had compensated cirrhosis and two patients had severe hepatitis C recurrence after liver transplantation. Severe pancytopenia was diagnosed a median of 10 wk after the initiation of therapy. Three patients had pre-treatment hematological abnormalities related to splenomegaly. In six patients, antiviral treatment was interrupted at the onset of hematological abnormalities. Two patients died due to septic complications and one patient due to acute alveolar hemorrhage. The remaining patients recovered. Severe pancytopenia and especially AA, are not rare during triple therapy with telaprevir in patients with advanced liver disease. Close monitoring is imperative in this setting to promptly detect serious hematological disorders and to prevent further complications.