Gian Paolo Caviglia

Outcome of chronic delta hepatitis in Italy: a long-term cohort study.

BACKGROUND & AIMS To investigate the impact of HDV infection on morbidity and mortality of patients. PATIENTS AND METHODS This was a retrospective study on 188 patients that underwent a program of periodic surveillance until 2008. The demographic data, stage of liver disease, treatment efficacy, development of liver complications (ascites, oesophageal bleeding, encephalopathy), and survival were registered. A Cox regression analysis was carried out to determine the impact of viral and patient features on survival. RESULTS At baseline, 126 patients (67%) tested positive for serum IgM anti-HDV antibodies, 171 (91%) for anti-HBe, 175 (93%) for serum HDV-RNA, and 61 (33%) for serum HBV-DNA. Eighty-two patients (43%) had chronic hepatitis at histology; the remaining 106 individuals had a clinical/histological diagnosis of cirrhosis. Ninety-six patients received interferon (n = 90) or lamivudine (n = 6) therapy, and 27 of them (30%) attained a sustained response. During follow up, 21 patients with chronic hepatitis progressed to cirrhosis. Of the 127 cirrhotic patients, hepatic decompensation occurred in 42 patients (33%) and hepatocellular carcinoma in 17 (13%). The 5- and 10-year survival free of events were 96.8% and 81.9%, respectively, for patients with chronic hepatitis, and 83.9% and 59.4% for cirrhotics (p<0.01). At multivariate analysis, lack of antiviral therapy (p = 0.01), cirrhosis at presentation (p<0.01), and male sex (p = 0.03) independently predicted a worse outcome. CONCLUSION HDV liver disease lasts several decades. Half of all patients who develop cirrhosis later will advance to liver failure. At present, interferon therapy is recommended as soon as possible to slow or alter the natural course of liver disease.

Association of ITPA polymorphisms rs6051702/rs1127354 instead of rs7270101/rs1127354 as predictor of ribavirin-associated anemia in chronic hepatitis C treated patients

Functional variants rs7270101 and rs1127354 of inosine triphosphatase (ITPA) were recently found to protect against ribavirin (RBV)-induced hemolytic anemia. However, no definitive data are yet available on the role of no functional rs6051702 polymorphism. Since a simultaneous evaluation of the three ITPA SNPs for hemolytic anemia has not yet been investigated, we aimed to understand the contribution of each SNPs and its potential clinical use to predict anemia in HCV treated patients. A retrospective analysis included 379 HCV treated patients. The ITPA variants rs6051702, rs7270101 and rs1127354 were genotyped and tested for association with achieving anemia at week 4. We also investigated, using multivariate logistic regression, the impact of each single and paired associated polymorphism on anemia onset. All SNPs were associated with Hb decrease. The carrier of at least one variant allele in the functional ITPA SNPs was associated with a lower decrement of Hb, as compared to patients without a variant allele. In multivariate logistic regression analyses the carrier of a variant allele in the rs6051702/rs1127354 association (OR=0.11, p=1.75×10(-5)) and Hb at baseline (OR=1.51, p=1.21×10(-4)) were independently associated with protection against clinically significant anemia at week 4. All ITPA polymorphisms considered were shown to be significantly associated with anemia onset. A multivariate regression model based on ITPA genetic polymorphisms was developed for predicting the risk of anemia. Considering the characterization of pre-therapy anemia predictors, rs6051702 SNP in association to rs1127354 is more informative in order to avoid this relevant adverse event.

Fecal calprotectin is an effective diagnostic tool that differentiates inflammatory from functional intestinal disorders.

Abstract Background. The clinical pictures of functional gastrointestinal disorders and inflammatory diseases can be quite similar leading to inappropriate and expensive investigations. Objective. To investigate fecal calprotectin (FC) diagnostic performance in different gastrointestinal conditions. Material and methods. Stool specimens of 66 outpatients referred for colonoscopy were collected for further FC determination. Diagnostic accuracy was assessed by the area under the curve (AUC). Sensitivity (Se), specificity (Sp), positive (PPV), and negative predictive values (NPV) were calculated according to the presence of inflammation and the main final diagnosis. Results. Histological inflammation was found in 45 (68%) patients: 24 had a diagnosis of inflammatory bowel disease (IBD) while 21 reported miscellaneous conditions (5 microscopic colitis, 2 eosinophilic colitis, and 14 nonspecific chronic colitis). The diagnosis in the 21 (32%) patients without inflammation was irritable bowel syndrome (IBS). Median FC values were 268 µg/g (95% CI, 151–343) and 49 µg/g (95% CI, 23–101) in patients with and without inflammation, respectively (p = 0.0001). AUC value of FC was 0.811 (Se = 68.9%, Sp = 71.4%, PPV = 83.8%, and NPV = 56.3% with a cutoff value of 100 µg/g) for discriminating between patients with and without inflammation and 0.931 (Se = 87.5%, Sp = 90.5%, PPV = 91.3%, and NPV = 86.4% with a cutoff value of 150 µg/g) for discriminating between patients with IBS and IBD. Using the cutoff value recommended by the manufacturer (50 µg/g), we found Se =100%, Sp =52.4%, PPV =70.6%, and NPV =100% for the diagnosis of IBD. Conclusions. FC appears to be a reliable noninvasive biomarker of intestinal inflammation useful to improve the appropriateness of colonoscopy requests.

Peripheral insulin resistance predicts liver damage in nondiabetic subjects with nonalcoholic fatty liver disease

Surrogate indexes of insulin resistance and insulin sensitivity are widely used in nonalcoholic fatty liver disease (NAFLD), although they have never been validated in this population. We aimed to validate the available indexes in NAFLD subjects and to test their ability to predict liver damage also in comparison with the NAFLD fibrosis score. Surrogate indexes were validated by the tracer technique (6,6‐D2‐glucose and U‐13C‐glucose) in the basal state and during an oral glucose tolerance test. The best‐performing indexes were used in an independent cohort of 145 nondiabetic NAFLD subjects to identify liver damage (fibrosis and nonalcoholic steatohepatitis). In the validation NAFLD cohort, homeostasis model assessment of insulin resistance, insulin to glucose ratio, and insulin sensitivity index Stumvoll had the best association with hepatic insulin resistance, while peripheral insulin sensitivity was most significantly related to oral glucose insulin sensitivity index (OGIS), insulin sensitivity index Stumvoll, and metabolic clearance rate estimation without demographic parameters. In the independent cohort, only oral glucose tolerance test‐derived indexes were associated with liver damage and OGIS was the best predictor of significant (≥F2) fibrosis (odds ratio = 0.76, 95% confidence interval 0.61‐0.96, P = 0.0233) and of nonalcoholic steatohepatitis (odds ratio = 0.75, 95% confidence interval 0.63‐0.90, P = 0.0021). Both OGIS and NAFLD fibrosis score identified advanced (F3/F4) fibrosis, but OGIS predicted it better than NAFLD fibrosis score (odds ratio = 0.57, 95% confidence interval 0.45‐0.72, P < 0.001) and was also able to discriminate F2 from F3/F4 (P < 0.003). Conclusion: OGIS is associated with peripheral insulin sensitivity in NAFLD and inversely associated with an increased risk of significant/advanced liver damage in nondiabetic subjects with NAFLD. (Hepatology 2016;63:107–116)

IL28B polymorphism genotyping as predictor of rapid virologic response during interferon plus ribavirin treatment in hepatitis C virus genotype 1 patients

AIM To clarify the association of interleukin-28B (IL28B) single nucleotide polymorphisms (SNPs) with hepatitis C virus (HCV) viremia changes for assessment of interferon (IFN) response. METHODS A cohort of 118 Caucasian treatment-naïve HCV-G1 infected patients, treated with pegylated-IFN alpha 2a or 2b associated with ribavirin (53 responders, 65 non-responders) during the period 2010-2012, were genotyped for IL28B SNPs rs12979860 C>T and rs8099917 T>G. Genotyping was performed by real-time allelic discrimination assay. Serum HCV RNA levels were assayed at 2, 4, 12, 24 and 48 wk during therapy. Correlation between IL28B genotypes and serum HCV RNA kinetics was investigated. Multivariable logistic regression analysis was performed to identify predictors of null-response. RESULTS Twenty-six out of 118 patients (22%) had no HCV RNA decline ≥ 1 log IU/mL at therapy week 4 (null-responders). IL28B genotype was rs8099917 (G)/rs1297860 in 21/26 (80%) of null-responder patients. Using multivariate analysis, it was shown that the presence of the rs8099917 G allele was the best predictor of null-response (OR = 7.9, 95%CI: 1.99-31.18). The presence of at least one favorable genotype showed a positive predictive value of above 90% for HCV RNA reduction ≥ log at week 4. Analysis of the HCV RNA kinetics during 12 wk of therapy in patients with IL28B rs12979860 CT heterozygosis (n = 73), according to their rs8099917 status, showed that the viremia reduction was significantly different in patients carrying the rs8099917 G allele compared to those with favorable homozygosis. CONCLUSION Our findings emphasize the association of the IL28B rs8099917 G allele with HCV. Genotyping for both IL28B SNPs is useful in clinical practice for thorough patient risk stratification based on IFN responsiveness.

Quantification of hepatitis B surface antigen with the novel DiaSorin LIAISON XL Murex HBsAg Quant: correlation with the ARCHITECT quantitative assays.

BACKGROUND Recent technologic innovations allow for quantitative assessment of hepatitis B surface antigen (HBsAg) levels in serum; this has been used to monitor the course of chronic HBV hepatitis (CHB) and predict treatment response. LIAISON-XL Murex HBsAg Quant assay (DiaSorin, Saluggia, I) is the newest immunoassay CE approved to quantify HBsAg. OBJECTIVES To compare LIAISON-XL performances with ARCHITECT-QT HBsAg (Abbott Diagnostics, IL, USA), as reference test. STUDY DESIGN Sequential serum samples (n=152) from 14 HBe-negative patients with CHB, the majority of them infected by HBV genotype D undergoing antiviral treatment, were retrospectively tested with both assays. The 2nd WHO Standard 00/588 for HBsAg was used as reference. RESULTS LIAISON-XL and ARCHITECT-QT correlated by r=0.95, p<0.0001; by Bland-Altman analysis agreement of mean difference was 0.21 ± 0.15 log 10 IU/mL, 95% CI: -0.07 to 0.5). Performance of LIAISON-XL against the 2nd WHO Standard was r=0.998, p<0.0001 (95% CI: 0.993-0.999) with results nearer to the expected WHO values compared to ARCHITECT-QT. Median baseline HBsAg level was similar with the two methods before antiviral treatment, throughout fluctuations of HBsAg level in treatment non-responders and during the decrease of HBsAg titer in treatment responders. Correlation between HBsAg levels and HBV DNA was statistically significant for both the two immunoassays (LIAISON-XL: r=0.4988, 95% CI: 0.3452-0.6264, p<0.0001; ARCHITECT-QT: r=0.480, 95% CI: 0.3233-0.6111, p<0.0001). CONCLUSIONS Correlation between HBsAg measurement with LIAISON-XL and ARCHITECT-QT was high. LIAISON-XL accurately quantified HBsAg in clinical samples at baseline or during antiviral therapy; it can be applied for HBsAg quantification in clinical practice and decision making in CHB.

Highly sensitive alpha‐fetoprotein, Lens culinaris agglutinin‐reactive fraction of alpha‐fetoprotein and des‐gamma‐carboxyprothrombin for hepatocellular carcinoma detection

Hepatocellular carcinoma (HCC) develops with high incidence in patients with chronic liver disease (CLD), and particularly in those with cirrhosis. Currently, diagnosis and surveillance are mainly based on imaging methods. The aim of this study was to evaluate the diagnostic accuracy of highly sensitive measurement of α‐fetoprotein (AFP), Lens culinaris agglutinin‐reactive fraction of AFP (AFP‐L3) and des‐γ‐carboxyprothrombin (DCP) alone and in combination, for HCC detection. In addition, a recently proposed statistical model, including these three biomarkers plus sex and age, the GALAD model, was applied.

Telaprevir-S isomer enhances ribavirin exposure and the ribavirin-related haemolytic anaemia in a concentration-dependent manner

The standard-of-care for the treatment of genotype-1 chronic hepatitis C is based on the combination of direct acting antivirals, such as boceprevir and telaprevir, with ribavirin and pegylated-interferon alfa. These triple regimens give a higher response rate than dual therapy, but on the other hand show a more than 10% higher rate of anaemia. Not enough focus has been given to the interaction between telaprevir and RBV. In this work, we aimed to study and deepen this relationship by comparing ribavirin plasma and intra-erythrocytic concentrations at one month of triple and dual therapy (17 vs. 119 patients). Moreover, we determined telaprevir isomers concentrations and tested them for correlation with ribavirin concentrations and haemoglobin loss at one month of treatment. Finally, all drugs concentration data were tested for their correlation with the renal function during treatment. The comparisons of ribavirin concentration and toxicity data were repeated on a sub-group of 9 patients who had been treated 1 year before with dual therapy and then re-treated with triple therapy. The observed ribavirin plasma and intra-erythrocytic concentrations in triple therapy were significantly higher compared to dual therapy, both in whole group and sub-group comparison. Ribavirin concentrations were significantly correlated to the haemoglobin loss and telaprevir-S isomer concentrations (r(2)=0.317 P(value)=0.023 and r(2)=0.388 P(value)=0.008, respectively). Renal function had a significant decrease from the baseline value, but was not significantly correlated with drugs concentrations. These results highlight for the first time that, in the context of triple therapy with telaprevir, ribavirin exposure is related to the telaprevir-S isomer plasma concentration. We conclude that the addition of telaprevir to the dual therapy increases ribavirin exposure and haemoglobin loss: this effect could probably be managed through the therapeutic drug monitoring of ribavirin and telaprevir-S concentrations.

Glucose breath test and Crohn's disease: Diagnosis of small intestinal bacterial overgrowth and evaluation of therapeutic response.

Abstract Objective. Small intestinal bacterial overgrowth (SIBO) is characterized by an abnormal proliferation of bacterial species in the small bowel. It has been shown that patients with Crohn’s disease (CD) have a higher risk of SIBO development. The aim of the present study was to investigate SIBO prevalence in CD patients, possible clinical predictors of SIBO development and response to antibiotic therapy. Material and methods. Sixty-eight patients (42 male, 26 female; mean age 49.3 ± 12.8 years) with CD reporting abdominal complaints were prospectively evaluated for SIBO with H2/CH4 glucose breath test (GBT). Results. Of the 68 patients enrolled, 18 (26.5%) tested positive for SIBO. Patients with SIBO exhibited increased stool frequency and significant reduction of stool solidity (p = 0.014), were older than patients tested negative to GBT (54.3 ± 13.0 years vs. 47.5 ± 12.3 years, p = 0.049), reported a longer history of CD (21.2 ± 10.3 years vs. 15.7 ± 10.2 years, p = 0.031) and showed a significant higher frequency of prior surgery (p = 0.001), revealing an association of number of surgical procedures (OR = 2.8315, 95% CI = 1.1525–6.9569, p = 0.023) with SIBO. Breath test normalization occurred in 13/15 patients evaluated after antibiotic and probiotic therapy. Although vitamin B12 levels were lower in patients with SIBO (p = 0.045) and a significant improvement was found after treatment (p = 0.011), this could be due to the heterogeneity, regarding vitamin B12 treatment, in our cohort. Conclusion. SIBO is a frequent but underestimated condition in CD, which often mimics acute flare, effectively identified with GBT and could be treated with a combined antibiotic and probiotic therapy.

Hepatitis B core‐related antigen kinetics in chronic hepatitis B virus genotype D‐infected patients treated with nucleos(t)ide analogues or pegylated‐interferon‐α

The aim of this study was to evaluate the correlation between hepatitis B core‐related antigen (HBcrAg) and hepatitis B virus (HBV) DNA and hepatitis B surface antigen (HBsAg) levels, and to investigate HBcrAg kinetics during nucleos(t)ide analogue (NA) or pegylated‐interferon (PEG‐IFN)‐α treatment in a cohort of chronic hepatitis B (CHB) genotype D patients.