Pietro Andreone

Telaprevir for retreatment of HCV infection.

BACKGROUND Up to 60% of patients with hepatitis C virus (HCV) genotype 1 infection do not have a sustained virologic response to therapy with peginterferon alfa plus ribavirin. METHODS In this randomized, phase 3 trial, we evaluated the addition of telaprevir to peginterferon alfa-2a plus ribavirin in patients with HCV genotype 1 infection who had no response or a partial response to previous therapy or who had a relapse after an initial response. A total of 663 patients were assigned to one of three groups: the T12PR48 group, which received telaprevir for 12 weeks and peginterferon plus ribavirin for a total of 48 weeks; the lead-in T12PR48 group, which received 4 weeks of peginterferon plus ribavirin followed by 12 weeks of telaprevir and peginterferon plus ribavirin for a total of 48 weeks; and the control group (PR48), which received peginterferon plus ribavirin for 48 weeks. The primary end point was the rate of sustained virologic response, which was defined as undetectable HCV RNA 24 weeks after the last planned dose of a study drug. RESULTS Rates of sustained virologic response were significantly higher in the two telaprevir groups than in the control group among patients who had a previous relapse (83% in the T12PR48 group, 88% in the lead-in T12PR48 group, and 24% in the PR48 group), a partial response (59%, 54%, and 15%, respectively), and no response (29%, 33%, and 5%, respectively) (P<0.001 for all comparisons). Grade 3 adverse events (mainly anemia, neutropenia, and leukopenia) were more frequent in the telaprevir groups than in the control group (37% vs. 22%). CONCLUSIONS Telaprevir combined with peginterferon plus ribavirin significantly improved rates of sustained virologic response in patients with previously treated HCV infection, regardless of whether there was a lead-in phase. (Funded by Tibotec and Vertex Pharmaceuticals; REALIZE ClinicalTrials.gov number, NCT00703118.).

Sustained virological response to interferon-α is associated with improved outcome in HCV-related cirrhosis: A retrospective study†‡

The effect of achieving a sustained virological response (SVR) following interferon‐α (IFNα) treatment on the clinical outcomes of patients with HCV‐related cirrhosis is unknown. In an attempt to assess the risk of liver‐related complications, HCC and liver‐related mortality in patients with cirrhosis according to the response to IFNα treatment, a retrospective database was developed including all consecutive patients with HCV‐related, histologically proven cirrhosis treated with IFNα monotherapy between January 1992 and December 1997. SVR was an undetectable serum HCV‐RNA by PCR 24 weeks after IFNα discontinuation. HCC was assessed by ultrasound every 6 months. Independent predictors of all outcomes were assessed by Cox regression analysis. Of 920 patients, 124 (13.5%) were classified as achieving a SVR. During a mean follow‐up of 96.1 months (range: 6‐167) the incidence rates per 100 person‐years of liver‐related complications, HCC and liver‐related death were 0, 0.66, and 0.19 among SVR and 1.88, 2.10, and 1.44 among non‐SVR (P < 0.001 by log‐rank test). Multivariate analyses found that non‐SVR was associated with a higher risk of liver‐related complications (hazard ratio, HR, not applicable), HCC (HR 2.59; 95% CI 1.13‐5.97) and liver‐related mortality (HR 6.97; 95% CI 1.71‐28.42) as compared to SVR. Conclusion: Thus, in patients with HCV‐related, histologically proven cirrhosis, achievement of a SVR after IFNα therapy was associated with a reduction of liver‐related mortality lowering both the risk of complications and HCC development. Irrespective of SVR achievement, all patients should continue surveillance because the risk of occurrence of HCC was not entirely avoided. (HEPATOLOGY 2007;45:579–587.)

Interferon and prevention of hepatocellular carcinoma in viral cirrhosis: an evidence-based approach

BACKGROUND/AIMS To evaluate by meta-analysis of available literature whether interferon (IFN) reduces the incidence of hepatocellular carcinoma (HCC) in patients with hepatitis B virus (HBV) or hepatitis C virus (HCV)-related Child A cirrhosis. METHODS Three randomized controlled trials and 15 nonrandomized controlled trials, including 4614 patients and comparing IFN to no treatment, were selected. Data on the incidence of HCC in IFN treated and untreated patients were extracted from each study. Meta-analysis by the DerSimonian and Laird risk difference (RD) method was used to pool observations. RESULTS A different incidence of HCC between treated and untreated cirrhotic patients was observed for HCV (overall RD -12.8%; 95% CI -8.3 to -17.2%, P < 0.0001) and HBV (overall RD -6.4%; 95% CI -2.8 to -10%, P < 0.001). In HCV-related cirrhosis, the rate of HCC development was lower in sustained responders to IFN than in untreated patients (overall RD -19.1%; 95% CI -13.1 to -25.2%, P < 0.00001), with low heterogeneity among trials (P=0.053), and also in nonresponders vs. untreated patients (overall RD -11.8%; 95% CI -6.4 to -19.1%, P < 0.0001), although with significant heterogeneity. Inconsistency among the studies was a major problem, both for HCV (chi2 = 58.16 with 13 DF; P < 0.0001) and HBV (chi2 = 26.4 with 6 DF; P = 0.0001) related cirrhosis, and also when follow-up was shorter than 60 months. Consistent results were only observed when assessing data from European reports: in this subgroup no preventive effect of HCC was shown for HBV (overall RD -4.8%; 95% CI -11.1-1.5%, P, not significant), and only a weak effect for HCV (overall RD -10%; 95% CI -5.9 to -14.2%; P < 0.0001). CONCLUSIONS Literature data pooling suggests a slight preventive effect of IFN on HCC development in patients with HCV-related cirrhosis. The magnitude of this effect is low and the observed benefit might be due to spurious associations. The preventive effect is more evident among sustained responders to IFN. IFN does not seem to affect the rate of HCC in HBV-related cirrhosis.

Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis

A genome-wide association screen for primary biliary cirrhosis risk alleles was performed in an Italian cohort. The results from the Italian cohort replicated IL12A and IL12RB associations, and a combined meta-analysis using a Canadian dataset identified newly associated loci at SPIB (P = 7.9 × 10−11, odds ratio (OR) = 1.46), IRF5-TNPO3 (P = 2.8 × 10−10, OR = 1.63) and 17q12-21 (P = 1.7 × 10−10, OR = 1.38).

ABT-450, Ritonavir, Ombitasvir, and Dasabuvir Achieves 97% and 100% Sustained Virologic Response With or Without Ribavirin in Treatment-Experienced Patients With HCV Genotype 1b Infection

BACKGROUND & AIMS The interferon-free regimen of ABT-450 (a protease inhibitor), ritonavir, ombitasvir (an NS5A inhibitor), dasabuvir (a non-nucleoside polymerase inhibitor), and ribavirin has shown efficacy in patients with hepatitis C virus (HCV) genotype 1b infection-the most prevalent subgenotype worldwide. We evaluated whether ribavirin is necessary for ABT-450, ritonavir, ombitasvir, and dasabuvir to produce high rates of sustained virologic response (SVR) in these patients. METHODS We performed a multicenter, open-label, phase 3 trial of 179 patients with HCV genotype 1b infection, without cirrhosis, previously treated with peginterferon and ribavirin. Patients were assigned randomly (1:1) to groups given ABT-450, ritonavir, ombitasvir, and dasabuvir, with ribavirin (group 1) or without (group 2) for 12 weeks. The primary end point was SVR 12 weeks after treatment (SVR12). We assessed the noninferiority of this regimen to the rate of response reported (64%) for a similar population treated with telaprevir, peginterferon, and ribavirin. RESULTS Groups 1 and 2 each had high rates of SVR12, which were noninferior to the reported rate of response to the combination of telaprevir, peginterferon, and ribavirin (group 1: 96.6%; 95% confidence interval, 92.8%-100%; and group 2: 100%; 95% confidence interval, 95.9%-100%). The rate of response in group 2 was noninferior to that of group 1. No virologic failure occurred during the study. Two patients (1.1%) discontinued the study owing to adverse events, both in group 1. The most common adverse events in groups 1 and 2 were fatigue (31.9% vs 15.8%) and headache (24.2% vs 23.2%), respectively. Decreases in hemoglobin level to less than the lower limit of normal were more frequent in group 1 (42.0% vs 5.5% in group 2; P < .001), although only 2 patients had hemoglobin levels less than 10 g/dL. CONCLUSIONS The interferon-free regimen of ABT-450, ritonavir, ombitasvir, and dasabuvir, with or without ribavirin, produces a high rate of SVR12 in treatment-experienced patients with HCV genotype 1b infection. Both regimens are well tolerated, as shown by the low rate of discontinuations and generally mild adverse events. ClinicalTrials.gov number: NCT01674725.

Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals

BACKGROUND & AIMS Hepatocellular carcinoma (HCC) represents a serious complication of HCV-related cirrhosis. New direct-acting antivirals (DAA) cure HCV infection in over 90% of patients. The aim of this study was to evaluate the early occurrence and recurrence of HCC in cirrhotic patients treated with DAA. METHODS We analysed 344 consecutive cirrhotic patients, without HCC, who were treated with DAA, and followed for 24weeks. Fifty-nine patients had previous HCC. RESULTS DAA therapy induced sustained virological response in 91% of patients. During 24-week follow-up, HCC was detected in 26 patients (7.6%, 95% CI: 4.99-10.84): 17 of 59 patients (28.81%, 95% CI: 17.76-42.07) with previous HCC and 9 of 285 patients (3.16%, 95% CI: 1.45-5.90) without previous HCC. Child-Pugh Class B, more severe liver fibrosis, lower platelet count, and previous HCC were significantly associated with HCC development, at univariate analysis. At multivariate analysis, Child-Pugh class (p=0.03, OR: 4.18, 95% CI: 1.17-14.8) and history of HCC (p<0.0001, OR: 12.0, 95% CI: 4.02-35.74) resulted independently associated with HCC development. Among the 59 patients with previous HCC, younger age and more severe liver fibrosis were significantly associated with HCC recurrence, both at univariate and at multivariate analysis. CONCLUSIONS In patients with HCV-related cirrhosis, DAA-induced resolution of HCV infection does not seem to reduce occurrence of HCC, and patients previously treated for HCC have still a high risk of tumour recurrence, in the short term. For these reasons, all cirrhotic patients should be closely monitored and followed during and after antiviral therapy. LAY SUMMARY New direct-acting antivirals are able to eradicate HCV infection in over 90% of patients with advanced liver disease. Unfortunately, the occurrence of liver cancer is not reduced in effectively treated cirrhotic patients. In addition, patients previously treated for HCC have still a high risk of tumour recurrence in the short term, despite DAA treatment.

Antiviral Intrahepatic T-Cell Responses Can Be Restored by Blocking Programmed Death-1 Pathway in Chronic Hepatitis B

BACKGROUND & AIMS The antiviral function of peripheral hepatitis B virus (HBV)-specific T cells can be increased in patients with chronic hepatitis B by blocking the interaction of programmed death (PD)-1 with its ligand PD-L1. However, no information is available about the effects of this blockade on intrahepatic lymphocytes. We studied T-cell exhaustion and the effects of PD-1/PD-L1 blockade on intrahepatic and circulating HBV-specific T cells in patients with chronic hepatitis B. METHODS A total of 42 patients with chronic HBV infection who underwent liver biopsy were studied. The ex vivo phenotype of peripheral and intrahepatic HBV-specific CD8(+) T cells was assessed by flow cytometry with class I tetramers and antibodies to T-cell differentiation molecules. Functional recovery was evaluated by analyzing expansion and production of interferon (IFN)-gamma and interleukin (IL)-2 after short-term incubation of T cells with HBV peptides in the presence of anti-PD-L1 or control antibodies. RESULTS Intrahepatic HBV-specific CD8(+) cells expressed higher levels of PD-1 and lower levels of CD127 than their peripheral counterparts. Blockade of PD-1/PD-L1 interaction increased CD8(+) cell proliferation and IFN-gamma and IL-2 production by circulating intrahepatic lymphocytes, even though anti-PD-L1 had a stronger effect on intrahepatic compared with peripheral T cells. CONCLUSIONS T-cell exhaustion by high antigen concentrations promotes HBV-specific T-cell dysfunction by affecting phenotype and function of peripheral and intrahepatic T cells. By restoring antiviral T-cell functions, not only in peripheral but also in intrahepatic lymphocytes, anti-PD-L1 might be a good therapeutic candidate for chronic HBV infection.

A Placebo-controlled trial of obeticholic acid in primary biliary cholangitis

BACKGROUND Primary biliary cholangitis (formerly called primary biliary cirrhosis) can progress to cirrhosis and death despite ursodiol therapy. Alkaline phosphatase and bilirubin levels correlate with the risk of liver transplantation or death. Obeticholic acid, a farnesoid X receptor agonist, has shown potential benefit in patients with this disease. METHODS In this 12-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 217 patients who had an inadequate response to ursodiol or who found the side effects of ursodiol unacceptable to receive obeticholic acid at a dose of 10 mg (the 10-mg group), obeticholic acid at a dose of 5 mg with adjustment to 10 mg if applicable (the 5-10-mg group), or placebo. The primary end point was an alkaline phosphatase level of less than 1.67 times the upper limit of the normal range, with a reduction of at least 15% from baseline, and a normal total bilirubin level. RESULTS Of 216 patients who underwent randomization and received at least one dose of obeticholic acid or placebo, 93% received ursodiol as background therapy. The primary end point occurred in more patients in the 5-10-mg group (46%) and the 10-mg group (47%) than in the placebo group (10%; P<0.001 for both comparisons). Patients in the 5-10-mg group and those in the 10-mg group had greater decreases than those in the placebo group in the alkaline phosphatase level (least-squares mean, -113 and -130 U per liter, respectively, vs. -14 U per liter; P<0.001 for both comparisons) and total bilirubin level (-0.02 and -0.05 mg per deciliter [-0.3 and -0.9 μmol per liter], respectively, vs. 0.12 mg per deciliter [2.0 μmol per liter]; P<0.001 for both comparisons). Changes in noninvasive measures of liver fibrosis did not differ significantly between either treatment group and the placebo group at 12 months. Pruritus was more common with obeticholic acid than with placebo (56% of patients in the 5-10-mg group and 68% of those in the 10-mg group vs. 38% in the placebo group). The rate of serious adverse events was 16% in the 5-10-mg group, 11% in the 10-mg group, and 4% in the placebo group. CONCLUSIONS Obeticholic acid administered with ursodiol or as monotherapy for 12 months in patients with primary biliary cholangitis resulted in decreases from baseline in alkaline phosphatase and total bilirubin levels that differed significantly from the changes observed with placebo. There were more serious adverse events with obeticholic acid. (Funded by Intercept Pharmaceuticals; POISE ClinicalTrials.gov number, NCT01473524; Current Controlled Trials number, ISRCTN89514817.).

Characteristics of hepatocellular carcinoma in Italy

BACKGROUND/AIMS This study aimed to assess the main features of hepatocellular carcinoma at the time of diagnosis in Italy, particularly in relation to the presence or absence of underlying cirrhosis, hepatitis virus marker patterns, age of the subjects and alpha-foetoprotein values. METHODS A total of 1148 patients with hepatocellular carcinoma seen at 14 Italian hospitals in the 1-year period from May 1996 to May 1997 were the subjects of this prevalence study. Both newly diagnosed cases (incident cases) and cases diagnosed before May 1996 but still attending the hospitals during the study period (prevalent cases) were included. RESULTS We found that 71.1% of cases were positive for hepatitis C virus antibodies but negative for HBsAg; in contrast, 11.5% were negative for anti-HCV but positive for HBsAg; 5.3% were positive for both markers; and 12.1% were negative for both viruses. The mean age of detection was over 60 years, with a younger mean age in HBsAg-positive compared to anti-HCV-positive patients (59.3 years vs. 65.6 years, p<0.01). The male-to-female ratio among HBsAg-positive patients was 10.4:1, in contrast to 2.8:1 among anti-HCV-positive patients (p<0.01). The majority of cases (93.1%) had underlying cirrhosis. Cirrhotic patients were more likely to be anti-HCV positive than non-cirrhotic cases (73.2% vs 43.9%; p<0.01); conversely, absence of hepatitis virus markers was more frequently observed in the non-cirrhotic than in the cirrhotic population (40.9% vs. 10.0%; p<0.01). Overall, the alpha-foetoprotein level was altered (>20 ng/ml) in 57.9% of patients; only 18% of cases presented diagnostic (>400 ng/ml) values. Anti-HCV positivity (O.R. 2.0; CI 95%=1.3-3.1) but not HBsAg positivity (O.R. 1.0; CI 95%=0.6-1.8) was shown to be an independent predictor of the likelihood of altered alpha-foetoprotein values by multivariate analysis. CONCLUSIONS These findings point to differences in the characteristics of the populations infected by hepatitis B and hepatitis C. Factors other than the hepatitis viruses are important in non-cirrhotic patients. A change in the relative prevalence of hepatitis virus markers among hepatocellular carcinoma cases was demonstrated, reflecting a significant change in the rate of HBV endemicity in the Italian population. Finally, the increased trend in the mortality rate from liver cancer in Italy from 4.8 per 100,000 in 1969 to 10.9 in 1994 may reflect the large cohort of subjects infected with HCV via the iatrogenic route during 1950s and 1960s when glass syringes were commonly used for medical treatment.

Silybin combined with phosphatidylcholine and vitamin E in patients with nonalcoholic fatty liver disease: A randomized controlled trial

The only currently recommended treatment for nonalcoholic fatty liver disease (NAFLD) is lifestyle modification. Preliminary studies of silybin showed beneficial effects on liver function. Realsil (RA) comprises the silybin phytosome complex (silybin plus phosphatidylcholine) coformulated with vitamin E. We report on a multicenter, phase III, double-blind clinical trial to assess RA in patients with histologically documented NAFLD. Patients were randomized 1:1 to RA or placebo (P) orally twice daily for 12 months. Prespecified primary outcomes were improvement over time in clinical condition, normalization of liver enzyme plasma levels, and improvement of ultrasonographic liver steatosis, homeostatic model assessment (HOMA), and quality of life. Secondary outcomes were improvement in liver histologic score and/or decrease in NAFLD score without worsening of fibrosis and plasma changes in cytokines, ferritin, and liver fibrosis markers. We treated 179 patients with NAFLD; 36 were also HCV positive. Forty-one patients were prematurely withdrawn and 138 patients analyzed per protocol (69 per group). Baseline patient characteristics were generally well balanced between groups, except for steatosis, portal infiltration, and fibrosis. Adverse events (AEs) were generally transient and included diarrhea, dysgeusia, and pruritus; no serious AEs were recorded. Patients receiving RA but not P showed significant improvements in liver enzyme plasma levels, HOMA, and liver histology. Body mass index normalized in 15% of RA patients (2.1% with P). HCV-positive patients in the RA but not the P group showed improvements in fibrogenesis markers. This is the first study to systematically assess silybin in NAFLD patients. Treatment with RA but not P for 12 months was associated with improvement in liver enzymes, insulin resistance, and liver histology, without increases in body weight. These findings warrant further investigation.