G. Mazzella

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.)

Serum α-fetoprotein for diagnosis of hepatocellular carcinoma in patients with chronic liver disease : influence of HBsAg and anti-HCV status

BACKGROUND It is not established whether virological status affects the efficiency of alpha-fetoprotein (AFP) as a hepatocellular carcinoma (HCC) marker among patients with chronic liver disease (CLD). METHODS We enrolled in a case-control study 170 HCC and 170 CLD patients, matched for age, sex, CLD and HBsAg/anti-HCV status. The AFP sensitivity, specificity, positive (PPV) and negative (NPV) predictive values were calculated. PPV and NPV were evaluated for three additional HCC prevalences (5, 10, and 20%). RESULTS The best discriminating AFP value was 16 ng/ml. A value of 20 ng/ml (above which investigations for HCC are recommended) had equivalent sensitivity (60.0 vs. 62.4%) and specificity (90.6 vs. 89.4%). PPV of 20 ng/ml was 84.6% but decreased to 25.1% at 5% tumor prevalence. NPV was 69.4% and rose to 97.7% at 5% prevalence. In the different groups of infected patients PPV ranged from 80.0 to 90.9%, falling to 17.4-34.5% at 5% prevalence. In noninfected patients PPV was 100% at any HCC prevalence. NPV ranged from 59.0 to 73.0%, reaching 96.5-98.1% at 5% prevalence. CONCLUSIONS In CLD patients, AFP monitoring misses many HCCs and inappropriately arouses suspicion of malignancy in many patients. Its usefulness is barely affected by the infection responsible for CLD. An AFP elevation could be more indicative of HCC in non-infected patients.

Alpha interferon treatment may prevent hepatocellular carcinoma in HCV-related liver cirrhosis

BACKGROUND/AIMS The aims of alpha-interferon treatment for chronic viral liver infections are clearance of the virus and healing of the disease. Hepatocellular carcinoma is a complication of viral cirrhosis; but it is not yet known whether treatment of viral cirrhosis with alpha-interferon prevents this complication. METHODS The incidence and the risk (Cox regression analysis) of developing hepatocellular carcinoma were calculated in 347 patients with hepatic cirrhosis; 227 (34 hepatitis B virus and 193 hepatitis C virus related) were treated with alpha-interferon and 120 (28 hepatitis B virus and 92 hepatitis C virus) did not receive this treatment, in order to evaluate the efficacy of alpha-interferon in the prevention of hepatocellular carcinoma. In all patients, the cirrhosis was well compensated (Child A). RESULTS Over mean follow-up periods of 49 months for hepatitis B virus and 32 months for hepatitis C virus, 20/347 patients (6/62 hepatitis B virus and 14/285 hepatitis C virus) developed hepatocellular carcinoma. The risk of developing this tumor was significantly greater in males (p < 0.007) and in patients not treated with alpha-interferon (p < 0.01). The Relative Risk of developing hepatocellular carcinoma increased significantly (p < 0.0002) with each passing year. In patients with hepatic cirrhosis secondary to hepatitis B virus infections, the risk did not seem to be modified by alpha-interferon treatment, even though a greater, but not significant risk (Relative Risk = 4.9; p = 0.3) was calculated for untreated patients; in contrast, in hepatitis C virus-related cirrhosis, this risk was reduced by a factor of 4.0 (p = 0.04). The tumor developed only in non-responder patients regardless of virus type. After adjustment for confounding factors (sex, age, alcohol consumption, cigarette smoking), a statistically significant (p < 0.025) effect of interferon treatment in preventing hepatocellular carcinoma was still demonstrated when responders were matched with controls, but not when responders were compared with non-responders. CONCLUSIONS These results show that, in addition to its ability to halt the progression of viral-induced liver disease, alpha-interferon is also of benefit in patients with hepatitis C virus cirrhosis who respond to this treatment by lowering their risk of developing hepatocellular carcinoma.

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.

The cyclophilin inhibitor Debio 025 combined with PEG IFNα2a significantly reduces viral load in treatment‐naïve hepatitis C patients

The anti–hepatitis C virus (HCV) effect and safety of three different oral doses of the cyclophilin inhibitor Debio 025 in combination with pegylated interferon‐α2a (PEG IFN‐α2a) were investigated in a multicenter, randomized, double‐blind, placebo‐controlled escalating dose‐ranging phase II study in treatment‐naïve patients with chronic hepatitis C. Doses of 200, 600, and 1,000 mg/day Debio 025 in combination with PEG IFN‐α2a 180 μg/week for 4 weeks were compared with monotherapy with either 1,000 mg/day Debio 025 or 180 μg/week PEG IFN‐α2a. In patients with genotypes 1 and 4, the 600‐ and 1,000‐mg combination treatments induced a continuous decay in viral load that reached −4.61 ± 1.88 and −4.75 ± 2.19 log10 IU/mL at week 4, respectively. In patients with genotypes 2 and 3, HCV RNA levels at week 4 were reduced by −5.91 ± 1.11 and −5.89 ± 0.43 log10 IU/mL, respectively, with the same treatment regimens. Adverse events were comparable between treatment groups apart from a higher incidence of neutropenia associated with PEG IFN‐α2a and an increased incidence of isolated hyperbilirubinemia at the highest dose of Debio 025 (1,000 mg/day). Conclusion: These results confirm that Debio 025 has a potent activity and an additive effect on HCV RNA reduction in genotype 1 and 4 patients at 600 and 1,000 mg/day when combined with PEG IFN‐α2a. (HEPATOLOGY 2009.)

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.).

Enzymatic determination of cholesterol in bile

Abstract A simple, sensitive and rapid method for measuring the cholesterol concentration in bile is described. The method is based on the combination of an enzymatic technique and spectrophotometry. In the present study the results obtained with this method are compared with those obtained by the standard Liebermann-Burchard reaction on the same samples and are found to be in close agreement.

Gallstone recurrence after successful oral bile acid treatment

Recurrence is a major problem in the medical treatment of gallstones but its extent is still uncertain. The aim of this study was to determine the magnitude of this event and to assess the effectiveness of a postdissolution treatment in preventing it. We evaluated the long-term recurrence rate after 96 confirmed dissolutions observed in 86 subjects (71 women, 15 men) over a 12-yr follow-up period. A low-dose postdissolution treatment (ursodeoxycholic acid, 300 mg/day) was administered to 36 subjects, whereas in the remaining 60 cases no postdissolution treatment was given. By actuarial life-table analysis, the cumulative proportion of gallstone recurrence was 12.5% at the first year, rising to 61% at the 11th year. Postdissolution treatment was effective in reducing the frequency of gallstone recurrence (p = 0.0067), but this was mainly related to its effect on younger subjects (less than or equal to 50 yr old). In older subjects the recurrence rate was unaffected by treatment. The probability of gallstone recurrence was significantly higher in subjects with multiple stones before dissolution treatment than in those who had had solitary stones (p = 0.0091). No other factor predictive of gallstone recurrence could be identified.

Gallbladder motility in cholesterol gallstone disease: Effect of ursodeoxycholic acid administration and gallstone dissolution

Gallbladder motility was evaluated by ultrasonography in 75 cholesterol gallstone patients and in 77 matched control subjects. All 75 gallstone patients were candidates for oral bile acid therapy (radiolucent gallstones, less than 2 cm in diameter, in well-opacified gallbladder), and 38 of them were also studied during ursodeoxycholic acid administration. An additional 20 gallstone patients were studied 1 year after confirmed gallstone dissolution with oral bile acids. Gallstone patients showed significantly greater fasting and residual volumes, a decreased percent of gallbladder emptying, but a similar absolute emptying and emptying rate compared with the control subjects. Greater fasting volumes and reduced percents of gallbladder emptying were also found in gallstone-free patients who achieved complete dissolution with oral bile acids. After ursodeoxycholic acid administration, fasting gallbladder volumes were greater, and percents of gallbladder emptying were further decreased than in untreated gallstone patients. In conclusion, greater fasting volumes, and not reduced gallbladder contractility, account for the defective gallbladder function in radiolucent (cholesterol-rich) gallstone patients. This condition is likely to precede, and possibly to promote, gallstone formation because it persists after gallstone dissolution. Ursodeoxycholic acid administration worsens the defect observed in gallstone patients. This finding also suggests, although indirectly, that the expected normalization of cholesterol saturation during oral bile acid administration is not paralleled by an improvement in gallbladder function.

High incidence of allograft dysfunction in liver transplanted patients treated with pegylated-interferon alpha-2b and ribavirin for hepatitis C recurrence: possible de novo autoimmune hepatitis?

Background: Interferon may trigger autoimmune disorders, including autoimmune hepatitis, in immunocompetent patients. To date, no such disorders have been described in liver transplanted patients. Methods: 9 of 44 liver transplanted patients who had been receiving pegylated-interferon alpha-2b and ribavirin for at least 6 months for hepatitis C virus (HCV) recurrence, developed graft dysfunction despite on-treatment HCV-RNA clearance in all but one case. Laboratory, microbiological, imaging and histological evaluations were performed to identify the origin of graft dysfunction. The International Autoimmune Hepatitis scoring system was also applied. Results: In all cases infections, anastomoses complications and rejection were excluded, whereas the autoimmune hepatitis score suggested a “probable autoimmune hepatitis” (score from 10 to 14). Three patients developed other definite autoimmune disorders (overlap anti-mitochondrial antibodies (AMA)-positive cholangitis, autoimmune thyroiditis and systemic lupus erythematosus, respectively). In all cases, pre-existing autoimmune hepatitis was excluded. Anti-lymphocyte antibodies in immunosuppressive induction treatment correlated with the development of the disorder, whereas the use of granulocyte colony-stimulating factor to treat interferon-induced neutropenia showed a protective role. Withdrawal of antiviral treatment and treatment with prednisone resulted in different outcomes (five remissions and four graft failures with two deaths). Conclusions: De novo autoimmune hepatitis should be considered in differential diagnosis along with rejection in liver transplanted patients developing graft dysfunction while on treatment with interferon.