F. Bronte

Comparison of transient elastography and acoustic radiation force impulse for non-invasive staging of liver fibrosis in patients with chronic hepatitis C.

OBJECTIVES:Transient elastography (TE) is adequate for a diagnosis of cirrhosis, but its accuracy for milder stages of fibrosis is much less satisfactory. The objective of this study was to compare the performance and the discordance rate of acoustic radiation force impulse (ARFI) and TE with liver biopsy in a cohort of chronic hepatitis C (CHC) patients.METHODS:One hundred thirty-nine consecutive patients with CHC were enrolled in two tertiary centers, and evaluated for histological (Metavir score) and biochemical features. All patients underwent TE and ARFI.RESULTS:TE was unreliable in nine patients (6.5%), while in no cases (0%) were ARFI invalid measurements recorded (P=0.029). By area under receiver operating characteristic curve (AUROC), the best cutoff values for TE and ARFI for significant fibrosis (≥F2) were ≥6.5 kPa (AUROC: 0.78) and ≥1.3 m/s (AUROC: 0.86), respectively. For severe fibrosis (F3–F4), these cutoff values were 8.8 kPa (AUROC: 0.83) for TE and 1.7 m/s (AUROC: 0.94) for ARFI. For cirrhosis, TE had its best cutoff at ≥11 kPa (AUROC: 0.80) and ARFI at ≥2.0 m/s (AUROC: 0.89). By pairwise comparison of AUROC, ARFI was significantly more accurate than TE for a diagnosis of significant and severe fibrosis (P=0.024 and P=0.002, respectively), while this difference was only marginal for cirrhosis (P=0.09). By partial AUROC analysis, ARFI performance results significantly higher for all three stages of fibrosis. The average concordance rates of TE and ARFI vs. liver biopsy were 45.4 and 54.7%, respectively. By multivariate analysis, ARFI was not associated with alanine aminotransferase (ALT), body mass index, Metavir grade, and liver steatosis, while TE was significantly correlated with the ALT value (P=0.027).CONCLUSIONS:In a cohort of patients with CHC, ARFI imaging was more accurate than TE for the non-invasive staging of both significant and severe classes of liver fibrosis.

Cost-effectiveness of boceprevir or telaprevir for untreated patients with genotype 1 chronic hepatitis C

Randomized controlled trials (RCTs) show that triple therapy (TT) with peginterferon alpha, ribavirin, and boceprevir (BOC) or telaprevir (TVR) is more effective than peginterferon‐ribavirin dual therapy (DT) in the treatment of previously untreated patients with genotype 1 (G1) chronic hepatitis C (CHC). We assessed the cost‐effectiveness of TT compared to DT in the treatment of untreated patients with G1 CHC. We created a Markov Decision Model to evaluate, in untreated Caucasian patients age 50 years, weight 70 kg, with G1 CHC and Metavir F2 liver fibrosis score, for a time horizon of 20 years, the cost‐effectiveness of the following five competing strategies: 1) boceprevir response‐guided therapy (BOC‐RGT); 2) boceprevir IL28B genotype‐guided strategy (BOC‐IL28B); 3) boceprevir rapid virologic response (RVR)‐guided strategy (BOC‐RVR); 4) telaprevir response‐guided therapy (TVR‐RGT); 5) telaprevir IL28B genotype‐guided strategy (TVR‐IL28B). Outcomes included life‐years gained (LYG), costs (in 2011 euros) and incremental cost‐effectiveness ratio (ICER). In the base‐case analysis BOC‐RVR and TVR‐IL28B strategies were the most effective and cost‐effective of evaluated strategies. LYG was 4.04 with BOC‐RVR and 4.42 with TVR‐IL28B. ICER compared with DT was €8.304 per LYG for BOC‐RVR and €11.455 per LYG for TVR‐IL28B. The model was highly sensitive to IL28B CC genotype, likelihood of RVR and sustained virologic response, and BOC/TVR prices. Conclusion: In untreated G1 CHC patients age 50 years, TT with first‐generation protease inhibitors is cost‐effective compared with DT. Multiple strategies to reduce costs and improve effectiveness include RVR or genotype‐guided treatment. (HEPATOLOGY 2012;56:850–860)

Insulin resistance is a risk factor for esophageal varices in hepatitis C virus cirrhosis

Indirect methods to predict the presence of esophageal varices (EV) in patients with cirrhosis are not sensitive enough to be used as a surrogate for endoscopy. We tested the effectiveness of liver stiffness measurement (LSM) by transient elastography and the presence of insulin resistance (IR), a marker associated with fibrosis progression, in the noninvasive prediction of portal hypertension. One hundred four consecutive patients with newly diagnosed Child A hepatitis C virus (HCV) cirrhosis underwent upper gastrointestinal endoscopy to search for EV. Clinical, anthropometric, biochemical, ultrasonographic, and metabolic features, including IR by the homeostasis model assessment (HOMA), and LSM by transient elastography, were recorded at the time of endoscopy. EVs were detected in 63 of 104 patients (60%). In 10 patients (16%), the EVs were medium‐large (≥F2). By multivariate analysis, the presence of EVs was independently associated with a low platelet count/spleen diameter ratio (OR, 0.998; 95% CI, 0.996‐0.999) and a high HOMA‐IR score (OR, 1.296; 95%CI, 1.018‐1.649), not with LSM (OR, 1.009; 95%CI, 0.951‐1.070). It is noteworthy that nine of ten patients with medium‐large EVs had a platelet/spleen ratio of less than 792 or an HOMA‐IR of greater than 3.5. The independent association between low platelet count/spleen diameter ratio (OR, 0.998; 95%CI, 0.996‐1.000), high HOMA‐IR score (OR, 1.373; 95%CI, 1.014‐1.859) and presence of EV was confirmed in the subgroup of 77 nondiabetic subjects. Conclusions: In patients with Child A HCV cirrhosis, two simple, easy‐to‐get tests, namely the platelet/spleen ratio and insulin resistance measured by HOMA‐IR, regardless of the presence of diabetes, significantly predict the presence of EV, outweighing the contribution given by transient elastography. (HEPATOLOGY 2009;49:195‐203)

Modified spleen stiffness measurement by transient elastography is associated with presence of large oesophageal varices in patients with compensated hepatitis C virus cirrhosis.

To evaluate the accuracy of liver transient elastography (TE), spleen TE and other noninvasive tests (AAR, APRI score, platelet count, platelet/spleen ratio) in predicting the presence and the size of oesophageal varices in compensated hepatitis C virus (HCV) cirrhosis, we studied 112 consecutive patients with compensated HCV cirrhosis who underwent biochemical tests, gastrointestinal endoscopy, liver TE and spleen TE by Fibroscan® (Echosens, Paris, France) using a modified software version with a range between 1.5 and 150 kPa. Spleen TE was not reliable in 16 patients (14.3%). Among the 96 patients with a valid measurement (69.8% men, mean age: 63.2 ± 9.5 years), 43.7% had no oesophageal varices, 29.2% had grade 1% and 27.1% had grade 2 or grade 3 oesophageal varices. Patients with values of 75 kPa by standard spleen TE had mean values of modified spleen TE of 117 kPa (range: 81.7–149.5). Linear regression revealed a significant correlation between modified spleen TE and oesophageal varix size (r = 0.501; beta: 0.763, SE: 0.144; P < 0.001). On univariate analysis, the variables associated with grade 2/grade 3 oesophageal varices were AAR score, APRI score, platelet/spleen ratio, liver TE and modified spleen TE. On multivariate analysis, only modified spleen TE (OR: 1.026; 95% CI: 1.007–1.046; P = 0.006) and AAR (OR: 14.725; 95% CI: 1.928–112.459; P = 0.010) remained independently associated with grade 2/grade 3 oesophageal varices. Platelet/spleen ratio was the best predictor of oesophageal varices area under the ROC curve (AUROC: 0.763, cut‐off: 800, sensitivity: 74%, specificity: 70%), while modified spleen TE was more accurate in predicting grade 2/grade 3 oesophageal varices (AUROC: 0.82, cut‐off: 54.0 kPa, sensitivity: 80%, specificity: 70%). Portal hypertension increases spleen stiffness, and the measurement of modified spleen TE is an accurate, noninvasive tool for predicting the presence of large oesophageal varices in patients with compensated HCV cirrhosis.

Noninvasive assessment of liver fibrosis in thalassaemia major patients by transient elastography (TE) – lack of interference by iron deposition

The correlation between liver stiffness, measured by transient elastography, liver fibrosis, using the histological METAVIR score, and iron overload, measured by atomic absorption spectrometry was evaluated in 56 homozygous‐β‐thalassaemics. Liver stiffness increased proportionally to liver fibrosis staging (r = 0·70; P > 0·001) independently of liver iron concentration (r = 0·01; P = 0·932). The area under the receiver‐operating characteristic curve for prediction of cirrhosis was 0·997 (95% confidence interval [CI]: 0·925–1·000) with cut‐off of 13 kPa with 100% sensitivity (95% CI: 69·0–100·0) and 95% specificity (95% CI: 84·2–99·3). Transient elastography is a reliable non‐invasive tool for diagnosing advanced liver fibrosis in homozygous‐β‐thalassaemics, regardless of the degree of iron overload.

IL28B polymorphisms influence stage of fibrosis and spontaneous or interferon-induced viral clearance in thalassemia patients with hepatitis C virus infection

Background Polymorphisms in the interleukin-28B are important determinants in the spontaneous and drug-induced control of hepatitis C virus infection. Design and Methods We assessed the association of rs8099917 and rs12979860 polymorphisms with spontaneous viral clearance, severity of liver fibrosis, and response to interferon-monotherapy in 245 thalassemia major patients with hepatitis C virus infection. Results Ninety-eight patients (40%) had a spontaneous viral clearance while 147 patients (60%) developed a chronic infection. Spontaneous viral clearance was more frequent among patients with the T/T genotype of rs8099917 polymorphism (OR 2.130; P=0.008) or C/C genotype of rs12979860 polymorphism (OR 2.425; P=0.001). During observation, 131 patients with chronic infection underwent a liver biopsy; age (OR 1.058; P=0.01) G/T or G/G genotypes of rs8099917 polymorphism (OR 3.962; P=0.001), and C/T or T/T genotypes of rs12979860 polymorphism (OR 3.494; P=0.005) were associated with severe liver fibrosis, independent of liver iron concentration. Finally, T/T genotype of rs8099917 polymorphism (OR 3.014; P=0.03) or C/C genotype of rs12979860 polymorphism (OR 3.285; P=0.01), age (OR 0.902; P=0.001), female gender (OR 3.418; P=0.01) and 2 or 3 virus C genotypes (OR 4.700; P=0.007) were independently associated with sustained virological response in 114 patients treated with alpha-interferon. Conclusions Polymorphisms in the interleukin-28B are associated with the control of hepatitis C virus infection in thalassemia major patients, and understanding allelic patterns has an important role in determining prognosis and therapeutic management.

Liver disease in chelated transfusion-dependent thalassemics: the role of iron overload and chronic hepatitis C

This study shows that hepatitis C virus infection is the main risk factor for liver fibrosis in chelated transfusion-dependent thalassemic patients. See related perspective article on page 1121. Iron overload and hepatitis virus C infection cause liver fibrosis in thalassemics. In a monocentric retrospective analysis of liver disease in a cohort of 191 transfusion-dependent thalassemics, in 126 patients who had undergone liver biopsy (mean age 17.2 years; 58 hepatitis virus C-RNA positive and 68 hepatitis virus C-RNA negative) the liver iron concentration (median 2.4 mg/gr dry liver weight) was closely related to serum ferritin levels (R = 0.58; p<0.0001). Male gender (OR 4.12) and serum hepatitis virus C-RNA positivity (OR 11.04) were independent risk factors for advanced liver fibrosis. The majority of hepatitis virus C-RNA negative patients with low iron load did not develop liver fibrosis, while hepatitis virus C-RNA positive patients infected with genotype 1 or 4 and iron overload more frequently developed advanced fibrosis. Hepatitis virus C infection is the main risk factor for liver fibrosis in transfusion-dependent thalassemics. Adequate chelation therapy usually prevents the development of liver fibrosis in thalassemics free of hepatitis virus C-infection and reduces the risk of developing severe fibrosis in thalassemics with chronic hepatitis C.

Fibrosis staging in chronic hepatitis C: analysis of discordance between transient elastography and liver biopsy

Summary.  In chronic hepatitis C, transient elastography (TE) accurately identifies cirrhosis, but its ability to assess significant fibrosis (Metavir ≥ F2) is variable. Constitutional and liver disease‐related factors may influence TE and here we examined the variables associated with differences. Three hundred consecutive hepatitis C virus (HCV)‐RNA positive patients had biochemical tests, TE and a biopsy performed on the same day. The Dale model was used to identify the variables associated with discordance between biopsy and elastography results. In 97 patients (34.2%), TE and histological assessment were discordant. Seventy‐six of 286 (26.6%) had stage ≥F2 and TE < 7.1 kPa (false negative); 21 of 286 (7.3%) had stage

Conquests and perspectives of cardio-oncology in the field of tumor angiogenesis-targeting tyrosine kinase inhibitor-based therapy

Introduction: Angiogenesis is fundamental for tumor development and progression. Hence, anti-angiogenic drugs have been developed to target VEGF and its receptors (VEGFRs). Several tyrosine kinase inhibitors (TKIs) have been developed over the years and others are still under investigation, each anti-VEGFR TKI showing a different cardiotoxic profile. Knowledge of the cardiac side-effects of each drug and the magnitude of their expression and frequency can lead to a specific approach. Areas covered: This work reviews the mechanism of action of anti-VEGFR TKIs and the pathophysiological mechanisms leading to cardiotoxicity, followed by close examination of the most important drugs individually. A literature search was conducted on PubMed selecting review articles, original studies and clinical trials, with a focus on Phase III studies. Expert opinion: Side-effects on the cardiovascular system could lead both to the worsening of general health status of cancer patients and to the discontinuation of the cancer treatment affecting its efficacy. Cardiologists often have to face new triggers of heart disease in these patients. They need a specific approach, which must be carried out in cooperation with oncologists. It must start before cancer treatment, continue during it and extend after its completion.

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.