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Background: High-dose peginterferon-α (PegIFN-α) induction and prolongation of therapy may be an option to improve sustained virological response (SVR) rates among hepatitis C virus (HCV) non-responders, although a higher and a longer dosing of PegIFN-α may intensify side effects. Methods: We randomized 53 patients, who previously failed with standard IFN-α±ribavirin, to a high-dose induction and an extended regimen with PegIFN-α-2b [3.0 μg/kg once weekly (q.w.) 12 weeks→2.0 μg/kg q.w. 12 weeks→1.5 μg/kg q.w. 48 weeks] or a standard regimen (1.5 μg/kg q.w. 48 weeks). All patients received daily weight-based ribavirin (800–1200 mg/day). The short-form 36 health survey was used to evaluate health-related quality of life (HRQL). Results: Intention-to-treat analysis showed no significant difference in SVR rate (44% vs. 37%, P=0.62) and relapse rate (9% vs. 31%, P=0.17) between experimental and standard treatment. Overall, 80% of the [positive predictive value (PPV)] patients with rapid virological response (RVR, HCV-RNA negativity at week 4) achieved SVR. No significant dose-related differences in HRQL were seen between both groups. At baseline, genotype 2 or 3 [odds ratio (OR): 7.4, 95% confidence interval (CI): 1.4–33.3, P=0.01] and γ-glutamyltransferase (GGT) levels <2 × ULN (upper limit of normal) (OR: 6.76, 95% CI: 1.5–31.3, P=0.009) were significantly associated with SVR. Multivariate logistic regression at week 4 showed that only baseline GGT <2 × ULN (OR: 7.3, 95% CI: 1.4–38.5, P=0.01) and RVR (OR: 15.6, 95% CI: 3.2–76.9, P<0.001) were independently predictive for SVR. Conclusion: Retreatment with PegIFN-α-2b and ribavirin for a minimum of 48 weeks should be considered in all patients unresponsive to previous IFN-based therapies. Baseline GGT values and RVR are highly predictive for retreatment outcome. [ABSTRACT FROM AUTHOR]

Discusses the pretreatment of intrahepatic CD8 cell count correlating to virological response to antiviral therapy in chronic hepatitis C virus infection. Virological response to baseline immune factors in some 17 patients; Measurement of intrahepatic CD8 cells present in the portal tract; Relationship between immune factor and therapeutic response.

Overall treatment results of chronic hepatitis C have improved markedly with the introduction of pegylated interferon-alpha (PEG–IFN-α) and ribavirin combination therapy. However, cure rates in the most common genotype 1 infection are still unsatisfactory. IFN-α dose–response studies on viral kinetics suggest that inadequate dosing might be a key factor but drug levels have hardly been tested, which is in part due to difficulties in measuring this cytokine in patient samples. We have shown recently that hepatitis C virus (HCV) replicons are highly sensitive to IFN-α. In this report we tested whether the replicon system could be used as a sensitive bioassay to determine the amount of biologically active IFN-α in serum or heparinized plasma of patients under therapy. To facilitate the measurements, a stably replicating subgenomic HCV RNA was developed that carries the gene encoding the firefly luciferase. Dose response studies with IFN-α demonstrate that the amount of expressed luciferase directly correlates with the level of HCV replication. By using this cell-based assay, serum samples of HCV patients treated with different types and doses of IFN-α were analyzed in parallel to IFN-α standards made by serial dilutions of the same type of IFN-α the patient was treated with. Based on nonlinear logistic models serum concentrations corresponding to 1.3–19 U/ml were determined in patients under standard or high dose IFN-α therapy, and from 3.8 to 4.1 ng/ml in patients treated with PEG IFN-α. In conclusion, the HCV-replicon based bioassay allows determining the levels of biologically active IFN-α in serum and heparinized plasma of patients under treatment. [Copyright &y& Elsevier]

Background & Aims In low-endemic countries it is debated whether first-generation migrants should be screened for chronic hepatitis B infection. We describe the clinical impact of five large-scale Dutch screening projects for hepatitis B in first-generation Chinese migrants. Methods Between 2009 and 2013 five independent outreach screening projects for hepatitis B targeting first-generation Chinese migrants were conducted in five main Dutch regions. To explore the relevance of our screening we defined clinical impact as the presence of an indication for: (i) antiviral therapy, (ii) strict follow-up because of high hepatitis B DNA levels and/or (iii) surveillance for hepatocellular carcinoma. Results In total, 4423 persons participated in the projects of whom 6.0% ( n = 264) were HBsAg positive. One hundred and twenty-nine newly diagnosed HBsAg-positive patients were analysed in specialist care. Among these patients prevalence of cirrhosis was 6.9% and antiviral therapy for hepatitis B was started in 32 patients (25%). In patients without a treatment indication, strict follow-up because of high hepatitis B DNA levels and/or surveillance for hepatocellular carcinoma was considered indicated in 64 patients (50%). Conclusions In our screening project in first-generation Chinese migrants, antiviral treatment, strict follow-up because of high hepatitis B DNA levels and/or surveillance for hepatocellular carcinoma were considered indicated in three of four analysed HBsAg-positive patients. These data show that detection of hepatitis B in Chinese migrants can have considerable impact on patient care. [ABSTRACT FROM AUTHOR]

Summary: Background: Autoimmune hepatitis requires long‐term therapy, and systemic corticosteroids are the backbone of therapeutic management. Prolonged use of corticosteroids may lead to adverse events but data from long‐term studies are mainly derived from studies in rheumatic diseases. Aim: To assess cataract, diabetes and fractures in relation to corticosteroid doses in the long‐term maintenance treatment of patients with autoimmune hepatitis. Methods: We retrospectively collected data on 476 patients (77% women) with an established diagnosis of autoimmune hepatitis. Binary logistic regression with a generalised estimating equation was used to analyse the association between current corticosteroid use and the incidence of cataract, diabetes and fractures with onset after autoimmune hepatitis diagnosis. We corrected for sex, age, cirrhosis at diagnosis and predniso(lo)ne use in the prior 3 years to account for possible ongoing effects. Results: A total of 6634 years, with a median of 13 (range 1‐40) per patient were recorded. The median age at diagnosis was 44 years (range 2‐88). Adverse events were documented in 120 (25%) patients. Low‐dose predniso(lo)ne (0.1‐5.0 mg/d) increased the odds of fractures whereas higher doses (>5.0 mg/d) increased the odds of cataracts and diabetes. Budesonide increased the odds of cataract and fractures; this effect was independent of predniso(lo)ne use in the prior 1, 2 or 3 years. Conclusions: Even low doses of corticosteroids frequently lead to substantial adverse events refuting the assumption that adverse events are prevented by administering low doses. [ABSTRACT FROM AUTHOR]

Background & Aims: HIV/hepatitis B virus (HBV) coinfected subjects are thought to have faster progression to end‐stage liver disease (ESLD) than HBV mono‐infected subjects. We assessed whether this remains in the current cART‐era. Methods: Data from subjects with follow‐up completion post‐2003 were compared between HIV/HBV coinfected subjects in the Dutch HIV Monitoring database and HBV mono‐infected subjects from two centres. The primary outcomes of composite ESLD included portal hypertension, decompensated cirrhosis, hepatocellular carcinoma, liver transplantation and liver‐related mortality. Outcomes were analysed using time‐dependent cause‐specific Cox regression models adjusted for follow‐up time and relevant covariates. Subset‐analyses were done in subjects with follow‐up pre‐2003. Results: In the 1336 co‐ vs 742 mono‐infected subjects, coinfected subjects had no increased probability for ESLD compared to mono‐infected subjects (cHR 0.7 (95% CI 0.4‐1.1), but had increased probabilities for all‐cause (cHR 7.4 [4.9‐11.1]) and liver‐related mortality (cHR 3.4 [1.6‐7.5]). In the current combined cohort, treatment with tenofovir or entecavir was inversely associated with ESLD, all‐cause and liver‐related mortality (cHR 0.4 [95% CI 0.3‐0.7], cHR 0.003 [0.001‐0.01]), cHR 0.007 [0.001‐0.05]). Other predictors for ESLD were older age, being of Sub‐Sahara African descent, increased alanine aminotransferase levels and hepatitis C virus coinfection. While the probability for all‐cause mortality was increased in coinfected subjects, this rate decreased compared to pre‐2003 (HR 40.2 (95% CI: 8.7‐186.2). Conclusions: HIV/HBV coinfected patients no longer seem to be at increased risk for progression to ESLD compared to HBV mono‐infected patients, likely due to widespread use of highly effective cART with dual HBV and HIV activity. [ABSTRACT FROM AUTHOR]

Summary: Background: Azathioprine (AZA) and mercaptopurine (MP) are the cornerstone of steroid‐sparing strategies in autoimmune hepatitis (AIH). Up to 20% of patients do not tolerate or respond to these regimens. Aim: To evaluate retrospectively the tolerability and efficacy of tioguanine (thioguanine) (TG) therapy in selected patients with AIH and AIH variant syndromes. Methods: Records of 52 patients who received TG therapy were retrieved from nine hospitals in the Netherlands. Indications for TG treatment were intolerable side effects on AZA or MP (n = 38), insufficient response (n = 11) or first‐line treatment (n = 3). Treatment efficacy was defined as normalisation of serum aminotransferases and serum immunoglobulin G. Results: No serious adverse events occurred in patients treated with TG during a median follow‐up of 18 months (range 1‐194). Treatment was well tolerated in 41 patients (79%), whereas four had tolerable (8%) and seven (13%) intolerable side effects. Thirty‐eight patients were treated with TG after intolerable side effects on AZA or MP; 29 patients continued TG therapy of whom 24 (83%) achieved complete biochemical remission, four (14%) had incomplete and one (3%) had no response; nine discontinued treatment. Seven of 11 patients with insufficient response to AZA or MP were responsive to TG, three with complete and four with incomplete biochemical remission; four discontinued due to intolerance (n = 2) and non‐response (n = 2). TG was effective in all AIH patients as first‐line maintenance treatment. Conclusion: In our retrospective review of TG therapy in selected patients with AIH or AIH variants who previously failed on AZA or MP, TG appeared tolerable with biochemical efficacy. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Chronic Hepatitis Cohort Study (CHeCS) Investigators. Infrequent clinical assessment of chronic hepatitis B patients in United States general healthcare settings" by P. R. Spradling and colleagues in the previous issue.

Background & Aims Single nucleotide polymorphisms ( SNP) in the Cytotoxic T lymphocyte antigen-4 gene ( CTLA-4) have been associated with several autoimmune diseases including autoimmune Hepatitis ( AIH). In this chronic idiopathic inflammatory liver disease, conflicting results have been reported on the association with a SNP at position +49 in the CTLA-4 gene in small patient cohorts. Here, we established the role of this SNP in a sufficiently large cohort of AIH patients. Methods The study population consisted of 672 AIH patients derived from academic and regional hospitals in the Netherlands and was compared with 500 controls selected from the 'Genome of the Netherlands' project cohort. Genotype frequencies were assessed by PCR for patients and by whole genome sequencing for controls. Results No significant differences in allele frequencies were found between patients and controls (G Allele: 40% vs 39%, P = 0.7). Similarly, no significant differences in genotype frequencies between patients and controls were found. Finally, there was no relation between disease activity and the G allele or AG and GG genotypes. Conclusion The Cytotoxic T Lymphocyte Antigen-4 +49 A/G polymorphism does not represent a major susceptibility risk allele for AIH in Caucasians and is not associated with disease severity at presentation. [ABSTRACT FROM AUTHOR]