Apurva A. Modi

The effects of discontinuing pioglitazone in patients with nonalcoholic steatohepatitis

A pilot study of a 48‐week course of pioglitazone demonstrated significant improvements in the biochemical and histological features of nonalcoholic steatohepatitis (NASH). The aim of the study was to assess the effects of stopping pioglitazone. Twenty‐one patients with NASH were treated with pioglitazone (30 mg/day) for 48 weeks and underwent baseline and end‐of‐treatment evaluation including liver biopsy. Thirteen patients were followed for at least 48 weeks after stopping therapy and 9 underwent repeat liver biopsy. Statistical comparisons were made to evaluate whether discontinuation of pioglitazone resulted in a reversal of improvements seen on therapy. Stopping pioglitazone was associated with subsequent elevation in serum alanine aminotransferase levels (from 34 ± 13 to 70 ± 39 IU/l), decrease in adiponectin (from 9.7 ± 9.1 to 5.1 ± 4.5 μg/ml), worsening insulin sensitivity (HOMA Index: from 2.9 ± 1.8 to 5.5 ± 5.4), and increase in total hepatic fat (from 30% ± 32% to 71% ± 33%) despite no change in average body weight compared to the end of treatment. Repeat liver biopsy in 9 patients revealed significant worsening of parenchymal inflammation (from 1.2 ± 0.7 to 2.9 ± 1.1) and steatosis (from 0.9 ± 0.6 to 2.1 ± 1.3) but no change in fibrosis (from 1.1 ± 1.2 to 1.2 ± 1.3). NASH was again present on liver biopsy in 7 patients. Conclusion: These findings suggest that long‐term therapy with pioglitazone may be necessary to maintain improvements in disease activity in patients with NASH, although weight gain during treatment may ultimately limit its beneficial effects. (HEPATOLOGY 2007.)

Increased caffeine consumption is associated with reduced hepatic fibrosis

Although coffee consumption has been associated with reduced frequency of liver disease, it is unclear whether the effect is from coffee or caffeine and whether there is an effect on hepatic fibrosis specifically. This study was undertaken to use a food‐frequency instrument for dietary caffeine consumption to evaluate the relationship between caffeine intake and liver fibrosis. Patients undergoing liver biopsy completed a detailed caffeine questionnaire on three occasions over a 6‐month period. Caffeine intake was compared between patients with mild and advanced liver fibrosis (bridging fibrosis/cirrhosis). Logistic regression was used to evaluate the association between caffeine consumption and hepatic fibrosis. One hundred seventy‐seven patients (99 male, 104 white, 121 with chronic hepatitis C virus [HCV] infection) undergoing liver biopsy completed the caffeine questionnaire on up to three occasions. Results from repeated questionnaires were consistent. Daily caffeine consumption above the 75th percentile for the cohort (308 mg = approximately 2.25 cups of coffee equivalents) was associated with reduced liver fibrosis (odds ratio [OR], 0.33; 95% confidence interval [CI], 0.14‐0.80; P = 0.015) and the protective association persisted after controlling for age, sex, race, liver disease, body mass index, and alcohol intake in all patients (OR, 0.25; 95% CI, 0.09‐0.67; P = 0.006), as well as the subset with HCV infection (OR, 0.19; 95% CI, 0.05‐0.66; P = 0.009). Despite a modest trend, consumption of caffeine from sources other than coffee or of decaffeinated coffee was not associated with reduced liver fibrosis. A reliable tool for measurement of caffeine consumption demonstrated that caffeine consumption, particularly from regular coffee, above a threshold of approximately 2 coffee‐cup equivalents per day, was associated with less severe hepatic fibrosis. (HEPATOLOGY 2010;51:201–209.)

Clinical trial: pilot study of metformin for the treatment of non-alcoholic steatohepatitis

Background  Non‐alcoholic steatohepatitis (NASH) is a form of progressive fatty liver disease that is strongly associated with insulin resistance, which suggests that insulin sensitizing agents such as metformin may be beneficial for NASH.

S-adenosyl methionine improves early viral responses and interferon-stimulated gene induction in hepatitis C nonresponders

BACKGROUND & AIMS Less than half of patients infected with hepatitis C virus (HCV) achieve sustained viral clearance after pegylated interferon (peginterferon) and ribavirin therapy. S-adenosyl methionine (SAMe) improves interferon signaling in cell culture. We assessed the effect of SAMe on the kinetics of the early antiviral response and interferon signaling in nonresponders to previous antiviral therapy and investigated the mechanisms involved. METHODS Nonresponders with HCV genotype 1 were given peginterferon alfa-2a and ribavirin for 2 weeks (course A, baseline/control). After 1 month, patients received SAMe (1600 mg daily) for 2 weeks and then peginterferon and ribavirin for 48 weeks (course B; completed by 21 of 24 patients). Viral kinetics and interferon-stimulated gene (ISG) expression in peripheral blood mononuclear cells (PBMCs) were compared between courses. RESULTS The decrease in HCV RNA from 0 to 48 hours (phase 1) was similar with and without SAMe. However, the second phase slope of viral decline was improved with SAMe (course A, 0.11 ± 0.04 log(10) IU/mL/wk; course B, 0.27 ± 0.06; P = .009); 11 patients (53%) achieved an early virological response, and 10 (48%) had undetectable HCV RNA by week 24. Induction of ISGs in PBMCs was significantly greater during course B. In cultured cells, SAMe increased induction of ISGs and the antiviral effects of interferon by increasing STAT1 methylation, possibly affecting STAT1-DNA binding. CONCLUSIONS The addition of SAMe to peginterferon and ribavirin improves the early viral kinetics and increases ISG induction in nonresponders to previous therapy. SAMe might be a useful adjunct to peginterferon-based therapies in chronic HCV infection.

New therapies for hepatitis C

No challenge in clinical hepatology is as great today as the management of patients with chronic hepatitis C who have failed to respond to an adequate course of antiviral therapy. At present, the optimal regimen is a combination of peginterferon and ribavirin.1 When given for 24 or 48 weeks, this combination results in a sustained eradication of hepatitis C virus (HCV) and a long-term remission of the disease in at least 75% of patients with genotype 2 or 3 HCV infection and in 40%-50% of those with genotype 1.2,3 Although impressive, these sustained virological response (SVR) rates leave as many as half of patients without benefit and with no means of ameliorating the subsequent course of the disease. Despite the importance of chronic hepatitis C (the leading cause of end-stage liver disease and need for liver transplantation in the Western world) and the intensity of the research on this viral infection, there have been no further improvements in response rates to therapy in many years. When will this change? In this issue of HEPATOLOGY, two original articles provide exciting new results on a novel orally available antiviral agent that has potent effects against HCV in vitro and in vivo.4,5 VX-950, now known as telaprevir, is a peptide-mimetic drug that was developed with structurebased drug design.6 Telaprevir is a specific, reversible inhibitor of the HCV genotype 1 serine protease encoded by the nonstructural 3 and 4A region of the viral genome. This protease is essential for HCV replication,7 and its inhibition in cell culture systems results in marked suppression of viral replication.6,7 In humans, telaprevir is orally available and causes a rapid and marked decrease in serum HCV RNA levels.8 In phase Ia studies using various doses and schedules, a dose of 750 mg of telaprevir given every 8 hours resulted in rapid 3-5 log10 decreases in serum HCV RNA levels in virtually all patients. Stopping therapy at 2 weeks led to a rapid return of HCV RNA to the pretreatment levels. These results suggest that longer term therapy might lead to the eradication of the virus in a high proportion of patients. However, even before the application of VX-950 to humans, the specter of antiviral drug resistance was raised. In replicon cell culture systems, the application of VX950 was found to select for HCV variants with drug resistance.9 Similar kinetics for the development of antiviral resistance were found for other inhibitors of the nonstructural 3 protease, although these variants had different specific mutations and mechanisms of resistance. These findings indicated that the long-term use of HCV protease inhibitors would probably require a combination therapy with other protease inhibitors, HCV polymerase inhibitors, or perhaps peginterferon with or without ribavirin. It was the last combination that was eventually pursued. In this issue of HEPATOLOGY, Forestier and her coinvestigators4 from Saarland University Hospital, the University of Amsterdam, and Vertex Pharmaceutics describe the preliminary clinical results of a small phase Ib trial of telaprevir.4 The report provides information on HCV RNA and alanine aminotransferase levels in 8 patients who received telaprevir alone, 8 who received telaprevir with peginterferon, and 4 who served as controls and received peginterferon alone for 2 weeks. Telaprevir was then stopped, but the patients were offered a continuation of treatment with a combination of peginterferon and ribavirin until 48 weeks and thus were provided the standard of care for chronic hepatitis C, genotype 1. Telaprevir led to a rapid decline in HCV RNA levels within 1-4 days. The combination of peginterferon with telaprevir resulted in a similar early decline in viral levels, but importantly, the combination therapy was associated with an additional, continuing decline after the first 4 days of treatment. At 14 days, the median decrease in HCV RNA was 5.5 log10 with telaprevir and peginterferon, 4.0 log10 with telaprevir alone, and only 1.1 log10 with peginterferon. These results suggest that peginterferon and telaprevir are synergistic (or at least additive) in their antiviral activity against HCV, and this finding is supported by cell culture results.10 The basis for the synergy between peginterferon and telaprevir is suggested by the second article in this issue on telaprevir by Kieffer and coworkers5 from Vertex Pharmaceuticals and the Johann Wolfgang von Goethe University Hospital at Frankfurt, who investigated variations in Abbreviations: HCV, hepatitis C virus; SVR, sustained virological response. Supported in part by the Intramural Division of the National Institute of Diabetes and Digestive and Kidney Diseases (National Institutes of Health). Apurva A. Modi and Jay H. Hoofnagle are employees of the National Institutes of Health (US Public Health Service, US Department of Health and Human Services). Address reprint requests to: Jay H. Hoofnagle, M.D., Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 31, Room 9A27, 31 Center Drive, Bethesda, MD 20892. E-mail: hoofnaglej@extra.niddk.nih.gov; fax: 301-480-7926. Copyright

Low- and standard-dose peginterferon alfa-2a for chronic hepatitis C, genotype 2 or 3: Efficacy, tolerability, viral kinetics and cytokine response

Aliment Pharmacol Ther 31, 1018–1027

W1143 Colonic Distribution of Mantle Cell Lymphoma

G A A b st ra ct s patients required contiguous organ resection, the most common of which were kidney (n=25), colon (n=14), and small bowel (n=6). 3.8% (n=6) of patients required vascular reconstruction. Multivariate logistic regression revealed ASA classification as an independent predictor of post-operative complications or death (composite endpoint, OR 3.23, CI 1.337.84). Pre-operative RT, creatinine, hematocrit, and albumin were not statistically significant. Similarly, extent of contiguous organ resection (OR 1.38, CI 0.49-3.89), nephrectomy (OR 1.73, CI 0.39-7.75), bowel resection (OR 0.29, CI 0.04-1.95), splenectomy (OR 2.19, CI 0.13-38.49), and vascular reconstruction (OR 3.77, CI 0.59-24.23) were not associated with increased 30-day morbidity or mortality. Conclusions: NSQIP data demonstrate acceptable rates of post-operative morbidity and mortality following RPS resection even in the setting of aggressive multivisceral resection. Contiguous organ resection should not be viewed as a contraindication to RPS resection.