Retreatment with pegylated interferon plus ribavirin of chronic hepatitis C non-responders to interferon plus ribavirin: A meta-analysis.

BACKGROUND/AIMS: Efficacy of retreatment with pegylated interferon (PEG-IFN) plus ribavirin of non-responders to standard or pegylated IFN plus ribavirin has been assessed in various studies, but sustained virologic response (SVR) rates are variable and factors influencing efficacy and tolerability still remain incompletely defined. We aimed to focus on SVR rates and to identify factors influencing them in this meta-analysis. METHODS: MEDLINE as well as a manual search were used. Studies were included if they were controlled or uncontrolled trials, if they had been published as full-length papers and if they included non-responders to standard or pegylated IFN and ribavirin therapy. Fourteen trials were included in the meta-analysis. Data on study populations, interventions, and outcomes were extracted from trials using a random-effects model. Primary outcome was the SVR rate. RESULTS: The pooled estimate of SVR rate was 16.3% (95% Confidence Interval - 95% CI, 8.3-29.6%). There was a significant heterogeneity among studies (p<0.0001). Heterogeneity was less apparent in studies that included fewer patients with cirrhosis or overweight. By meta-regression, higher SVR rate was observed in trials with a lower prevalence of subjects with genotype 1 infection and with fewer overweight patients. The use of a 24-week retreatment stopping rule did not affect SVR rate. CONCLUSIONS: The overall modest efficacy argues against an indiscriminate retreatment with PEG-IFN and ribavirin of all non-responders. Restricting retreatment to non-overweight patients or to those with genotype 2 or 3 infection, using a 24-week retreatment stopping rule, would optimize the potential benefit with a scarce likelihood of missing a curative response

Systemic treatment for hepatocellular carcinoma beyond milan criteria on the waitlist: is it time for a neoadjuvant therapy?

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Fecal calprotectin in clinical practice: a noninvasive screening tool for patients with chronic diarrhea

Background: Surrogate markers of colorectal inflammation are increasingly being recognized as important in differentiating organic from functional intestinal disorders. Fecal calprotectin (FC) can be easily measured in the stool, being released by leukocytes in inflammatory conditions. Aim: We evaluated FC as an index of inflammation in consecutive outpatients referred for colonoscopy for chronic, nonbloody diarrhea. Methods: Stool specimens of 346 outpatients with chronic, nonbloody diarrhea, referred for colonoscopy, were measured for FC levels. The proportion of patients correctly diagnosed with the test and the relationship with endoscopic and histologic findings were measured. Results: Abnormal endoscopic findings were detected in 104 patients (30.1%). Histologic findings included 142 patients (41.0%) with inflammation and 204 (59.0%) without inflammation. Fecal excretion of calprotectin significantly correlated with the finding of inflammation at endoscopy and histology (P<0.0001). When 150 mcg/g of stool was used as the upper reference limit, FC showed 75.4% sensitivity and 88.3% specificity, with 81.7% positive and 83.7% negative predictive values for histologic inflammation. Conclusions: In outpatients referred for colonoscopy a measurement of FC is accurate to identify those with histologic inflammation. Assay of FC may be a reliable and noninvasive screening tool to identify inflammatory causes of chronic, nonbloody diarrhe

CT enterography as a powerful tool for the evaluation of inflammatory activity in Crohn's disease: relationship of CT findings with CDAI and acute-phase reactants

Few studies have correlated computed tomography enterography (CTE) findings with Crohn's disease (CD) clinical and biochemical activity. The aim of this study was to evaluate correlations between CTE findings with CD activity.The CTE datasets from 62 patients were retrospectively reviewed for different parameters: bowel wall thickening and hyperenhancement, mesenteric alterations, abdominal free fluid and complications related to the disease (fistulas, strictures, abscesses). Activity was assessed using the Crohn's Disease Activity Index (CDAI) and some biochemical markers (C-reactive protein, erythrocyte sedimentation rate, alpha 2-globulins, fibrinogen, platelets, haemoglobin). Correlations between CTE parameters, clinical activity score and laboratory parameters were assessed by logistic regression.CDAI was significantly correlated with increased fat density (p = 0.03) and intestinal strictures (p = 0.04). Platelet counts were elevated in patients with enlarged mesenteric lymph nodes (p = 0.009) and the comb sign (p = 0.05). Serum alpha 2-globulins were higher in the presence of the comb sign (p = 0.03).The CTE finding of perienteric inflammation (increased fat density) and vascular engorgement of the vasa recta in CD patients suggest that the disease is clinically active and that these patients may require more aggressive treatment than patients without these findings

Prioritization of high-cost new drugs for HCV: making sustainability ethical

Hepatitis C virus (HCV) infection is a major health problem worldwide. Chronic HCV infection may in the long run cause cirrhosis, hepatic decompensation and hepatocellular carcinoma, with an ultimate disease burden of at least 350,000 deaths per year worldwide. The new generation of highly effective direct acting antivirals (DAA) to treat HCV infection brings major promises to infected patients in terms of exceedingly high rates of sustained virological response (SVR) but also of tolerability, allowing even the sickest patients to be treated. Even in the face of the excellent safety and efficacy and wide theoretical applicability of these regimens, their introduction is currently facing cost and access issues denying their use to many patients in need. Health systems in all countries are facing a huge problem of distributive justice, since while they should guarantee individual rights, among which the right to health in its broader sense, therefore not limited to healing, but extended to quality of life, they must also grant equal access to the healthcare resources and keep the distribution system sustainable. In the face of a disease with a relatively unpredictable course, where many but not of all chronically infected will eventually die of liver disease, selective allocation of this costly resource is debatable. In most countries the favorite solution has been a stratification of patients for prioritization of treatment, which means allowing Interferon-free DAA treatment only in patients with advanced fibrosis or cirrhosis, while keeping on hold persons with lesser stages of liver disease. In this report, we will perform an ethical assessment addressing the issues linked to access to new therapies, prioritization and eligibility criteria, analyzing the meaning of the term “distributive justice” and the different approaches that can guide us (individualistic libertarianism, social utilitarianism and egalitarianism) on this specific matter. Even if over time the price of new DAA will be reduced through competition and eventual patent expiration, the phenomenon of high drug costs will go on in the next decades and we need adequate tools to face the problems of distributive justice that come with it

Visceral adiposity index is associated with significant fibrosis in patients with non-alcoholic fatty liver disease

Background: Metabolic factors have been associated with liver damage in patients with non-alcoholic fatty liver disease (NAFLD). Aims To test a new marker of adipose dysfunction, the visceral adiposity index (VAI), in NAFLD patients to assess whether or not it is associated with host factors, and to investigate a potential correlation with histological findings. Methods One hundred and forty-two consecutive NAFLD patients were evaluated by liver biopsy, and clinical and metabolic measurements, including insulin resistance with the homeostasis model assessment (HOMA), and VAI by using waist circumference, body mass index, triglycerides and HDL. Serum levels of TNF\u3b1, IL-6, adiponectin and leptin were also assessed. All biopsies were scored for NAFLD activity score (NAS) and its components, and for staging (Kleiner). Results By multiple linear regression analysis, VAI was independently associated with higher HOMA (P = 0.04), and fibrosis (P = 0.04). In addition, an independent association was found between higher VAI and lower adiponectin levels (P = 0.002). Higher HOMA (OR 1.149, 95% CI 1.003-1.316, P = 0.04), higher VAI (OR 1.446, 95% CI 1.023-2.043, P = 0.03), lobular inflammation (OR 3.777, 95% CI 1.771-8.051, P = 0.001), and ballooning (OR 2.884, 95% CI 1.231-6.757, P = 0.01) were correlated with significant fibrosis (F2-F4) on multiple logistic regression analysis. In particular, the prevalence of significant fibrosis progressively increased from patients with a VAI 64 2.1 and HOMA 64 3.4 (26%) to those with a VAI > 2.1 and HOMA > 3.4 (83%). Conclusions In NAFLD patients, visceral adiposity index is an expression of both qualitative and quantitative adipose tissue dysfunction and, together with insulin resistance, is independently correlated with significant fibrosis. \ua9 2011 Blackwell Publishing Ltd

First-Line Immune Checkpoint Inhibitor-Based Sequential Therapies for Advanced Hepatocellular Carcinoma: Rationale for Future Trials

Atezolizumab (ATEZO) plus bevacizumab (BEVA) represents the new standard of care for the treatment of advanced hepatocellular carcinoma (HCC). However, the choice of the second-line treatment after the failure of immunotherapy-based first-line remains elusive. Taking into account the weaknesses of the available evidence, we developed a simulation model based on available phase III randomized clinical trials (RCTs) to identify optimal risk/benefit sequential strategies. Methods: A Markov model was built to estimate the overall survival (OS) of sequential first- and second-line systemic treatments. Sequences starting with first-line ATEZO plus BEVA followed by 5 second-line treatments (sorafenib [SORA], lenvatinib [LENVA], regorafenib, cabozantinib, and ramucirumab) were compared. The probability of transition between states (initial treatment, cancer progression, and death) was derived from RCTs. Life-year gained (LYG) was the main outcome. Rates of severe adverse events (SAEs) (≥ grade 3) were calculated. The incremental safety-effectiveness ratio (ISER) was calculated as the difference in probability of SAEs divided by LYG between the 2 most effective sequences. Results: ATEZO plus BEVA followed by LENVA (median OS, 24 months) or SORA (median OS, 23 months) was the most effective sequence, producing a LYG of 0.50 and 0.42 year, respectively. ATEZO plus BEVA followed by SORA was the safest sequence (SAEs 63%). At a willingness-to-risk threshold of 10% of SAEs for LYG, ATEZO plus BEVA followed by second-line SORA was favored in 72% of cases, while at a threshold of 30% of SAEs for LYG, ATEZO plus BEVA followed by second-line LENVA was favored in 69% of cases. Conclusion: Our simulation model provides a strong rationale to support ongoing trials evaluating second-line tyrosine-kinase inhibitors after first-line ATEZO plus BEVA. Future evidence from ongoing RCTs and prospective real-world studies are needed to prove the net health benefit of sequential treatment options for advanced HCC

Hepatic steatosis and insulin resistance are associated with severe fibrosis in patients with chronic hepatitis caused by HBV or HCV infection.

BACKGROUND AND AIMS: Steatosis and insulin resistance (IR) are the major disease modifying in patients with chronic hepatitis C (CHC). Only few studies evaluated these features in patients with chronic hepatitis B (CHB). We aimed to assess the prevalence and the factors related to steatosis and IR in CHB patients, compared with CHC subjects, and to evaluate the potential association between these features and fibrosis severity. MATERIAL AND METHODS: One hundred and seventy consecutive patients with CHB (28 HBeAg positive, 142 HBeAg negative), were evaluated using liver biopsy and metabolic measurements and matched for sex, age and body mass index with 170 genotype 1 CHC patients. IR was defined if HOMA-IR>2.7. All biopsies were scored for grading and staging by Scheuer's score, and the steatosis was considered significant if ≥ 10%. RESULTS: The prevalence of significant steatosis was similar in both CHB and CHC patients (31 vs. 38%; P=0.14). IR rate was significantly higher in CHC than in CHB patients (42 vs. 26%; P=0.002). Severe fibrosis (F3-F4), at multivariate analysis, was independently associated with older age (OR 1.050, 95% CI 1.009-1.093), steatosis >10% (OR 4.375, 95% CI 1.749-10.943), and moderate-severe necroinflammatory activity (OR 8.187, 95% CI 2.103-31.875), regardless of HBeAg status, in CHB patients, and with older age (OR 1.080, 95% CI 1.028-1.136), IR (OR 2.640, 95% CI 1.110-6.281), steatosis >10% (OR 3.375, 95% CI 1.394-8.171), and moderate-severe necroinflammatory activity (OR 8.988, 95% CI 1.853-43.593) in CHC patients. CONCLUSIONS: CHB patients had high steatosis prevalence, similar to CHC controls, but lower IR rate. Both steatosis and IR in CHC, and only steatosis in CHB, are independently associated with fibrosis severity