Serum anti-interferon alpha antibodies in chronic hepatitis C patients treated with pegylated interferon alpha containing therapy

The development of anti-IFNα antibodies is an occurrence described in chronic hepatitis C patients during treatment with Interferonα/PEG-Interferonα. However, its relevance, especially in difficult-to treat patients, has not been defined. Methods: We retrospectively measured the serum levels of anti-IFNα antibodies (baseline and week 12) and IFNα levels (week 12) by ELISA in 76 previous non-responders, and in 14 naive patients treated with Pegylated-IFNα and Ribavirin. A group of 57 healthy donors (HD) was also assessed as control. Positivity to anti-IFNα antibodies was established on the values of HD. Results: Baseline anti-IFNα antibodies were detected in 15.5% of patients and in 7% of HD, with significantly higher concentrations in patients than HD (181.5±389.9 vs 95.9±143.0 ng mL−1, p=0.0023). All positive patients were IFNα-experienced. At week 12, the prevalence of positivity increased to 22.3 and 28.5% in experienced and naïve patients, respectively, and the levels of anti-IFNα antibodies did not differ between the two groups (391±792.3 vs 384.7±662.6 ng mL−1, respectively). IFNα concentrations were significantly lower in antibody-positive patients than in antibody-negatives (988.2±1402 vs 3462±830.8 pg mL−1, p≤0.0001) and the levels of antibodies and IFNα were inversely correlated (r=-0.405, p=0.0001). The antibody-positive population clustered in null responders (67%) and 19/21 patients (90%) did not achieve SVR. Conclusions: The development of anti-IFNα antibodies is a non-negligible occurrence in patients treated with PEG-IFNα, is stable over time, and has a relevant clinical impact when associated with low levels of circulating PEG-IFNα. It should be considered in patients undergoing treatments including PEG-IFNα

Immune inflammation indicators and ALBI score to predict liver cancer in HCV-patients treated with direct-acting antivirals

Background: Unexpectedly high occurrence or recurrence rate of hepatocellular carcinoma (HCC) has been observed in patients with chronic hepatitis C receiving direct-acting antivirals (DAAs) therapy. Aims: We evaluated the predictive value of albumin-bilirubin (ALBI) score and immune-inflammation indicators to identify the risk of occurrence or recurrence of HCC in patients treated with DAAs in a real life setting. Methods: In this retrospective cohort study, we analysed data from 514 patients with cirrhosis who were prospectively enrolled for treatment with DAAs. We assessed baseline neutrophil to lymphocyte ratio (NLR), systemic immune-inflammation index (SII), platelet to lymphocyte ratio (PLR), aspartate aminotransferase-lymphocyte ratio (ALRI) index and ALBI score. Results: In patients with no history of HCC (N = 416), increased AST, bilirubin, ALRI, and ALBI score, and decreased albumin and platelets were significantly associated with an increased risk of HCC development, at univariate analysis. At multivariate analysis, increase in ALBI grade (p = 0.038, HR: 2.35, 95% CI: 1.05\u20135.25) and decrease in platelets (p = 0.048, HR: 0.92, 95% CI: 0.85\u20131.0) were independently associated with HCC development. In patients with previous HCC (N = 98), adjusting for the time from HCC treatment, increased ALRI (p = 0.008, HR: 1.05, 95% CI: 1.01\u20131.09) was significantly associated with a risk of recurrence. Conclusion: ALBI score, platelet count and ALRI are promising, easy to perform and inexpensive tools for identifying patients with higher risk of HCC after treatment with DAAs

Utility of neutrophil-to-lymphocyte ratio to identify long-term survivors among HCC patients treated with sorafenib

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ANGPT2 and NOS3 Polymorphisms and Clinical Outcome in Advanced Hepatocellular Carcinoma Patients Receiving Sorafenib

Sorafenib represents the standard of care for advanced hepatocellular carcinoma (HCC), even though a large number of patients have reported limited ecacy. The aim of the present study was to evaluate the prognostic value of single-nucleotide polymorphisms on angiopoietin-2 (ANGPT2) and endothelial-derived nitric oxide synthase (NOS3) genes in 135 patients with advanced HCC receiving sorafenib. Eight ANGPT2 polymorphisms were analyzed by direct sequencing in relation to overall survival (OS) and progression-free survival (PFS). In univariate analysis, ANGPT2rs55633437 and NOS3 rs2070744 were associated with OS and PFS. In particular, patients with ANGPT2rs55633437 TT/GT genotypes had significantly lower median OS (4.66 vs. 15.5 months, hazard ratio (HR) 4.86, 95% CI 2.73\u20138.67, p < 0.001) and PFS (1.58 vs. 6.27 months, HR 4.79, 95% CI 2.73\u20138.35, p < 0.001) than those homozygous for the G allele. Moreover, patients with NOS3 rs2070744 TC/CC genotypes had significantly higher median OS (15.6 vs. 9.1 months, HR 0.65, 95% CI 0.44\u20130.97; p = 0.036) and PFS (7.03 vs. 3.5 months, HR 0.43, 95% CI 0.30\u20130.63; p < 0.001) than patients homozygous for the T allele. Multivariate analysis confirmed these polymorphisms as independent prognostic factors. Our results suggest that ANGPT2rs55633437 and NOS3 rs2070744 polymorphisms could identify a subset of HCC patients more resistant to sorafenib

Validation and refinement of PROSASH model using the neutrophil‐to‐lymphocyte ratio in patients with HCC receiving sorafenib

AbstractThe recently developed PROSASH model is proving to be a useful tool in risk‐group discrimination in hepatocellular carcinoma (HCC) patients treated with sorafenib. Several studies highlighted that the neutrophil‐to‐lymphocyte ratio (NLR) is one of the most important predictors of survival in HCC patients treated with sorafenib. The aims of the present study were to validate the PROSASH model and determine whether the incorporation of inflammatory markers can improve risk stratification. This study included 438 patients. According to the four categories of the PROSASH model, median overall survival (OS) was 20.0, 14.9, 8.5 and 3.0 months respectively (P < .001). The Harrell's c for this categorized model was 0.621. NLR (cut‐off 3) stratified OS in each of the PROSASH categories. After reclassification, median OS was 21.0, 15.1, 8.2 and 4.1 months (P < .001). The Harrell's c increased from 0.621 to 0.673 (P = .001). Integrating NLR into the PROSASH model allowed a more accurate classification of the patients in the risk groups

Hepatitis C virus eradication in the elderly: The challenge worth a long-life elixir?

No abstract availabl

Managing HCV treatment failure and the potential of resistance testing in informing second-line therapy options

Introduction: Direct acting antivirals have completely changed the landscape of the treatment of chronic hepatitis C. The management of the few patients who relapse to direct acting antivirals requires a careful analysis of the chances to achieve therapeutic success with a second antiviral course. In this context, the usefulness of viral resistances testing, able to detect resistance-associated substitutions in the viral sequence, is at present a matter of debate. Areas covered: The role of resistance associated substitutions is examined through the evaluation of the data from clinical trials that have assessed the impact of viral resistances on the treatment outcome. Special attention has been paid on the data from re-treatment studies. Expert commentary: The treatment failure in chronic hepatitis C is still a possible event. Therefore, additional real-world clinical data on relapse rates and on the relapse management are welcome to definitely address the clinical guidelines. At present, the testing of viral resistances is an exquisite tool for the choice of the re-treatment schedule. In the near future, widespread use of the most recently registered direct acting antivirals with high barrier to resistance will probably weaken the need of resistance testing as a support in clinical decisions

Prospective, observational real-life study on eligibility for and outcomes of antiviral treatment with peginterferon \u3b1 plus ribavirin in chronic hepatitis C

Background: We aimed to investigate eligibility, reasons for treatment discontinuation and characteristics of chronic hepatitis C patients with treatment failure to peginterferon/ribavirin in clinical practice. Methods: 1128 chronic hepatitis C patients, from 45 Italian Hepatology centres, were enrolled in this phase-4, prospective, observational study from January 2009 to February 2010. Results: 687/1118 patients (61.4%) were eligible for antiviral treatment, of which 598 (87.0%) agreed with the physician's decision. Outcome information was available in 500/598 patients, among whom 348 (69.6%) completed treatment. Treatment was discontinued in 152 patients due to: lack of response (28.9%), personal reasons (29.6%), adverse events (38.2%), and decompensation (1.3%). Sustained virological response was obtained in 263/500 (52.6%), 71 (14.2%) relapsed and 61 (12.2%) were non-responders. Treatment outcome was not available in 105 (21%): lost while receiving treatment (33.3%), lost during follow-up (25.7%), withdrawn for adverse events (19.1%) or for administrative reasons (21.9%). Conclusion: In clinical practice, only 61% of chronic hepatitis C patients are considered eligible for peginterferon/ribavirin. Of these, 13% refuse treatment. Approximately 30% do not complete the scheduled treatment and, despite this, the sustained virological response rate is similar to that of randomized-controlled trials. In the era of new antiviral combinations, these findings have important implications for assessing eligibility and estimating drop-out rates

De novo autoimmune hepatitis in liver transplant: State-of-the-art review

In the two past decades, a number of communications, case-control studies, and retrospective reports have appeared in the literature with concerns about the development of a complex set of clinical, laboratory and histological characteristics of a liver graft dysfunction that is compatible with autoimmune hepatitis. The de novo prefix was added to distinguish this entity from a pre-transplant primary autoimmune hepatitis, but the globally accepted criteria for the diagnosis of autoimmune hepatitis have been adopted in the diagnostic algorithm. Indeed, de novo autoimmune hepatitis is characterized by the typical liver necroinflammation that is rich in plasma cells, the presence of interface hepatitis and the consequent laboratory findings of elevations in liver enzymes, increases in serum gamma globulin and the appearance of nonorgan specific auto-antibodies. Still, the overall features of de novo autoimmune hepatitis appear not to be attributable to a univocal patho-physiological pathway because they can develop in the patients who have undergone liver transplantation due to different etiologies. Specifically, in subjects with hepatitis C virus recurrence, an interferon-containing antiviral treatment has been indicated as a potential inception of immune system derangement. Herein, we attempt to review the currently available knowledge about de novo liver autoimmunity and its clinical management

Non-alcoholic steatohepatitis and liver transplantation

Non-alcoholic steatohepatitis is a growing liver-related health problem. In Europe, non-alcoholic fatty liver disease is the most usual reason of chronic liver illness while steatohepatitis, its progressive form, affects 1% of Europeans and North Americans. In the United States steatohepatitis-related cirrhosis is one of the main indications for liver transplant. A targeted stratification for patients waiting for transplant and affected by this disease is mandatory especially because of their increased cardiovascular and cancer risk. The adequate treatment of NAFLD is crucial for the reduction of the disease related morbidity and mortality. In post-transplant setting, the recurrent or de novo steatosis might seriously affect the allograft short- and long-term outcome. Many conditions can represent the basis of the post-transplant steatohepatitis: obesity, hyperlipidaemia, diabetes mellitus, arterial hypertension, immunosuppressant treatment, alcoholic habit and liver graft steatosis. Today, the only consolidated therapy is represented by a deep life-style intervention since the use of drug-based alternative strategies is still limited and a very few data are available for the post-transplant period. Targeted and personalized behaviour and pharmacological interventions have to be developed for both the pre- and post-transplant phase