Zachary D. Goodman

Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial

BACKGROUND A sustained virological response (SVR) rate of 41% has been achieved with interferon alfa-2b plus ribavirin therapy of chronic hepatitis C. In this randomised trial, peginterferon alfa-2b plus ribavirin was compared with interferon alfa-2b plus ribavirin. METHODS 1530 patients with chronic hepatitis C were assigned interferon alfa-2b (3 MU subcutaneously three times per week) plus ribavirin 1000-1200 mg/day orally, peginterferon alfa-2b 1.5 microg/kg each week plus 800 mg/day ribavirin, or peginterferon alfa-2b 1.5 microg/kg per week for 4 weeks then 0.5 microg/kg per week plus ribavirin 1000-1200 mg/day for 48 weeks. The primary endpoint was the SVR rate (undetectable hepatitis C virus [HCV] RNA in serum at 24-week follow-up). Analyses were based on patients who received at least one dose of study medication. FINDINGS The SVR rate was significantly higher (p=0.01 for both comparisons) in the higher-dose peginterferon group (274/511 [54%]) than in the lower-dose peginterferon (244/514 [47%]) or interferon (235/505 [47%]) groups. Among patients with HCV genotype 1 infection, the corresponding SVR rates were 42% (145/348), 34% (118/349), and 33% (114/343). The rate for patients with genotype 2 and 3 infections was about 80% for all treatment groups. Secondary analyses identified bodyweight as an important predictor of SVR, prompting comparison of the interferon regimens after adjusting ribavirin for bodyweight (mg/kg). Side-effect profiles were similar between the treatment groups. INTERPRETATION In patients with chronic hepatitis C, the most effective therapy is the combination of peginterferon alfa-2b 1.5 microg/kg per week plus ribavirin. The benefit is mostly achieved in patients with HCV genotype 1 infections.

Interferon Alfa-2b Alone or in Combination with Ribavirin as Initial Treatment for Chronic Hepatitis C

BACKGROUND Only 15 to 20 percent of patients with chronic hepatitis C have a sustained virologic response to interferon therapy. We compared the efficacy and safety of recombinant interferon alfa-2b alone with those of a combination of interferon alfa-2b and ribavirin for the initial treatment of patients with chronic hepatitis C. METHODS We randomly assigned 912 patients with chronic hepatitis C to receive standard-dose interferon alfa-2b alone or in combination with ribavirin (1000 or 1200 mg orally per day, depending on body weight) for 24 or 48 weeks. Efficacy was assessed by measurements of serum hepatitis C virus (HCV) RNA and serum aminotransferases and by liver biopsy. RESULTS The rate of sustained virologic response (defined as an undetectable serum HCV RNA level 24 weeks after treatment was completed) was higher among patients who received combination therapy for either 24 weeks (70 of 228 patients, 31 percent) or 48 weeks (87 of 228 patients, 38 percent) than among patients who received interferon alone for either 24 weeks (13 of 231 patients, 6 percent) or 48 weeks (29 of 225 patients, 13 percent) (P<0.001 for the comparison of interferon alone with both 24 weeks and 48 weeks of combination treatment). Among patients with HCV genotype 1 infection, the best response occurred in those who were treated for 48 weeks with interferon and ribavirin. Histologic improvement was more common in patients who were treated with combination therapy for either 24 weeks (57 percent) or 48 weeks (61 percent) than in those who were treated with interferon alone for either 24 weeks (44 percent) or 48 weeks (41 percent). The drug doses had to be reduced and treatment discontinued more often in patients who were treated with combination therapy. CONCLUSIONS In patients with chronic hepatitis C, initial therapy with interferon and ribavirin was more effective than treatment with interferon alone.

Lamivudine as Initial Treatment for Chronic Hepatitis B in the United States

BACKGROUND AND METHODS Although the nucleoside analogue lamivudine has shown promise in patients with chronic hepatitis B, long-term data on patients from the United States are lacking. We randomly assigned previously untreated patients with chronic hepatitis B to receive either 100 mg of oral lamivudine or placebo daily for 52 weeks. We then followed them for an additional 16 weeks to evaluate post-treatment safety and the durability of responses. The primary end point with respect to efficacy was a reduction of at least 2 points in the score on the Histologic Activity Index. On this scale, scores can range from 0 (normal) to 22 (most severe abnormalities). RESULTS Of the 143 randomized patients, 137 were included in the efficacy analysis: 66 in the lamivudine group and 71 in the placebo group. The other six patients were excluded at the base-line visit because of the absence of a documented history of hepatitis B surface antigen for at least six months. After 52 weeks of treatment, lamivudine recipients were more likely than placebo recipients to have a histologic response (52 percent vs. 23 percent, P<0.001), loss of hepatitis B e antigen (HBeAg) in serum (32 percent vs. 11 percent, P=0.003), sustained suppression of serum hepatitis B virus (HBV) DNA to undetectable levels (44 percent vs. 16 percent, P<0.001), and sustained normalization of serum alanine aminotransferase levels (41 percent vs. 7 percent, P<0.001), and they were less likely to have increased hepatic fibrosis (5 percent vs. 20 percent, P=0.01). Lamivudine recipients were also more likely to undergo HBeAg seroconversion, defined as the loss of HBeAg, undetectable levels of serum HBV DNA, and the appearance of antibodies against HBeAg (17 percent vs. 6 percent, P=0.04). HBeAg responses persisted in most patients for 16 weeks after the discontinuation of treatment. Lamivudine was well tolerated. Self-limited post-treatment elevations in serum alanine aminotransferase were more common in lamivudine recipients: 25 percent had serum alanine aminotransferase levels that were at least three times base-line levels, as compared with 8 percent of placebo recipients (P=0.01). The clinical condition of all patients remained stable during the study. CONCLUSIONS In U.S. patients with previously untreated chronic hepatitis B, one year of lamivudine therapy had favorable effects on histologic, virologic, and biochemical features of the disease and was well tolerated. HBeAg responses were generally sustained after treatment.

Recombinant interferon alfa therapy for chronic hepatitis C. A randomized, double-blind, placebo-controlled trial.

Infection with the hepatitis C virus may result in chronic liver disease for which no effective therapy is now available. We studied the effects of recombinant human interferon alfa in a prospective, randomized, double-blind, placebo-controlled trial in patients with well-documented chronic hepatitis C. Forty-one patients were enrolled in the trial, 37 of whom were later found to have antibody to hepatitis C virus. Twenty-one patients received interferon alfa (2 million units) subcutaneously three times weekly for six months, and 20 received placebo. The mean serum aminotransferase levels and the histologic features of the liver improved significantly in the patients treated with interferon but not in the patients given placebo. Ten patients treated with interferon (48 percent) had a complete response, defined as a decline in mean serum aminotransferase levels to the normal range during therapy; three others had a decrease in mean aminotransferase levels of more than 50 percent. After treatment ended, however, serum aminotransferases usually returned to pretreatment levels; 6 to 12 months after the discontinuation of interferon therapy, only two patients (10 percent) still had normal values. We conclude that interferon alfa therapy is beneficial in reducing disease activity in chronic hepatitis C; however, the beneficial responses are often transient.

Rates and risk factors of liver fibrosis progression in patients with chronic hepatitis c.

BACKGROUND AIMS In hepatitis C there is controversy over the linearity of the rate of progression and the significance of gender, mode of infection and viral factors. METHODS 2313 untreated patients with a reliable estimated duration of infection and liver fibrosis were included. Fibrosis progression was calculated using the Kaplan-Meier method and the rate of fibrosis progression using the hazard function. Seven risk factors were assessed: age at biopsy, gender, alcohol consumption, mode of infection, activity grade, hepatitis C virus genotype and RNA level. RESULTS The percentage of patients without cirrhosis was 91% after 20 years of infection (95% CI:90-92%) and 56% after 40 years (95% CI:48-64%). Three independent factors were associated (P < 0.001) with a faster progression rate: age at infection, alcohol consumption of 50 g or more per day, and male gender. The mode of infection, histologic activity, genotype and viral load were not independently associated with fibrosis. Fibrosis progression was mainly dependent on age and the duration of infection and can be divided into four successive periods with very slow, slow, intermediate and rapid progression rates. CONCLUSION In patients infected with hepatitis C, the majority of fibrosis progression occurred in those aged fifty years or older.

Long‐term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B

One year of treatment with entecavir (0.5 mg daily) in nucleoside‐naive patients with hepatitis B e antigen (HBeAg)‐positive or HBeAg‐negative chronic hepatitis B (CHB) resulted in significantly improved liver histology and virological and biochemical endpoints in comparison with lamivudine. Patients who received at least 3 years of cumulative entecavir therapy in phase 3 studies and a long‐term rollover study and underwent long‐term liver biopsy were evaluated for improvements in histological appearance. Sixty‐nine patients [50 HBeAg‐positive and 19 HBeAg‐negative] receiving entecavir therapy underwent long‐term liver biopsy (median time of biopsy = 6 years, range = 3‐7 years). Histological improvement was analyzed for 57 patients who had adequate baseline biopsy samples, baseline Knodell necroinflammatory scores ≥2, and adequate long‐term biopsy samples. At the time of long‐term biopsy, all patients in the cohort had a hepatitis B virus DNA level <300 copies/mL, and 86% had a normalized alanine aminotransferase level. Histological improvement (≥2‐point decrease in the Knodell necroinflammatory score and no worsening of the Knodell fibrosis score) was observed in 96% of patients, and a ≥1‐point improvement in the Ishak fibrosis score was found in 88% of patients, including all 10 patients with advanced fibrosis or cirrhosis at the phase 3 baseline. Conclusion: The majority of nucleoside‐naive patients with CHB who were treated with entecavir in this long‐term cohort achieved substantial histological improvement and regression of fibrosis or cirrhosis. (HEPATOLOGY 2010)

Incidence of Hepatocellular Carcinoma and Associated Risk Factors in Hepatitis C-Related Advanced Liver Disease

BACKGROUND & AIMS Although the incidence of hepatocellular carcinoma (HCC) is increasing in the United States, data from large prospective studies are limited. We evaluated the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) cohort for the incidence of HCC and associated risk factors. METHODS Hepatitis C virus-positive patients with bridging fibrosis or cirrhosis who did not respond to peginterferon and ribavirin were randomized to groups that were given maintenance peginterferon for 3.5 years or no treatment. HCC incidence was determined by Kaplan-Meier analysis, and baseline factors associated with HCC were analyzed by Cox regression. RESULTS 1,005 patients (mean age, 50.2 years; 71% male; 72% white race) were studied; 59% had bridging fibrosis, and 41% had cirrhosis. During a median follow-up of 4.6 years (maximum, 6.7 years), HCC developed in 48 patients (4.8%). The cumulative 5-year HCC incidence was similar for peginterferon-treated patients and controls, 5.4% vs 5.0%, respectively (P= .78), and was higher among patients with cirrhosis than those with bridging fibrosis, 7.0% vs 4.1%, respectively (P= .08). HCC developed in 8 (17%) patients whose serial biopsy specimens showed only fibrosis. A multivariate analysis model comprising older age, black race, lower platelet count, higher alkaline phosphatase, esophageal varices, and smoking was developed to predict the risk of HCC. CONCLUSIONS We found that maintenance peginterferon did not reduce the incidence of HCC in the HALT-C cohort. Baseline clinical and laboratory features predicted risk for HCC. Additional studies are required to confirm our finding of HCC in patients with chronic hepatitis C and bridging fibrosis.

Hepatobiliary cystadenoma and cystadenocarcinoma. A light microscopic and immunohistochemical study of 70 patients

Fifty-two hepatobiliary cystadenomas and 18 hepatobiliary cystadenocarcinomas were drawn from the files of the Armed Forces Institute of Pathology and Rhode Island Hospital and studied in an attempt to correlate light microscopic features of the tumors with immunohistochemical and follow-up data. The cystadenoma patients ranged in age from 2 to 87 years at the time of initial diagnosis (mean, 45 years). All the cystadenomas were multilocular with benign cuboidal to columnar epithelium, and 44 (85%) had densely cellular spindle cell (“ovarian-like”) stromata; 96% were female. Fifty-one cystadenomas were macrocystic lesions, typically lined by mucinous epithelium; one of the benign lesions was a serous cystadenoma (microcystic adenoma) reminiscent of the more commonly encountered pancreatic lesion of the same name. The cystadenocarcinoma patients ranged in age from 24 to 90 years at the time of first diagnosis (mean, 59 years); eight patients (44%) were male. All but one of the lesions were multilocular with malignant in situ (one case) or invasive tubulopapillary (15 cases), solid (one case), or adenosquamous (one case) epithelial components. Areas of preexisting benign cystadenoma were found in six (33%), an observation suggesting that benign lesions may evolve into malignant ones in some patients. Most cystadenomas and cystadenomas and cystadenocarcinomas arose in the liver, a few in the extrahepatic biliary system (including the gallbladder). On follow-up, the cystadenoma patients in general were successfully treated by surgical excision of the lesions in toto; patients treated by subtotal resection often had persistent symptomatic disease. Four cystadenocarcinoma patients died of their tumors; another two patients were alive with persistent disease at last follow-up. In both the benign and the malignant lesions, most tumor cells were positive on immunohistochemical staining with antibodies to cytokeratin. epithelial membrane antigen, and carcinoembryonic antigen; scattered chromogranin-positive cells also appeared in a few tumors of both types. Immunohistochemistry did not yield a diagnostic immunoprofile to distinguish cystadenoma from cystadenocarcinoma or from other epithelial lesions arising within the abdominal cavity. At least two types of cystadenocarcinoma exist, one developing exclusively in female patients, usually accompanied by an “ovarian-like” stroma, which follows an indolent course:and the other, lacking the distinctive cellular stroma, seen in males, follows a more aggress ve course and is more likely to result in the patients death from tumor. It remains an open question whether the cystadenocarcinomas lacking a mesenchymal stroma, which arise in women, will follow the same aggressive course as similar lesions arising in men.

Combined hepatocellular-cholangiocarcinoma. A histologic and immunohistochemical study.

Combined hepatocellular‐cholangiocarcinoma is a rare form of primary liver cancer showing features of both hepatocellular and biliary epithelial differentiation. In a review of 24 cases of this tumor, three histologic types were encountered. Four cases were Type I or “collision tumors,” apparently a coincidental occurrence of both hepatocellular carcinoma and cholangiocarcinoma in the same patient. Twelve cases were Type II or “transitional tumors,” in which there were areas of intermediate differentiation and an identifiable transition between hepatocellular carcinoma and cholangiocarcinoma. Eight cases were Type III or “fibrolamellar tumors” which resembled the fibrolamellar variant of hepatocellular carcinoma but which also contained mucin‐producing pseudoglands. Type III tumors differ from other combined tumors, occurring at a younger age, in the absence of cirrhosis, and having a slightly longer survival. Immunohistochemical (immunoperoxidase) staining for intracellular antigens showed that alpha‐fetoprotein is a fairly specific, although insensitive, marker of hepatocellular differentiation in primary liver cancers, being present in 50% of typical hepatocellular carcinomas and in hepatocellular areas in 29% of combined tumors, but in no cholangiocarcinomas or cholangiocellular areas of combined tumors. Keratin is a good marker of biliary epithelial differentiation, being found in 90% of cholangiocarcinomas and in 52% of combined hepatocellular cholangiocarcinomas, but in no hepatocellular carcinomas. Alpha‐1‐antitrypsin, fibrinogen, IgG, and carcinoembryonic antigen may be found in both hepatocellular carcinoma, cholangiocarcinoma, and in combined tumors; these antigens are therefore of limited use in differential diagnosis.

Adipokines and cytokines in non‐alcoholic fatty liver disease

Background  Several adipocytokines have been implicated in the pathogenesis non‐alcoholic fatty liver disease (NAFLD).