Edward Lebovics

A Randomized Trial of Pegylated Interferon α-2b Plus Ribavirin in the Retreatment of Chronic Hepatitis C

OBJECTIVES:The efficacy of combination therapy with pegylated interferon (PEG IFN) α plus ribavirin (RBV) in the retreatment of chronic hepatitis C (CHC) in patients who previously failed combination standard IFN plus RBV or IFN monotherapy has not been well established.METHODS:Three hundred and twenty-one CHC patients including virologic nonresponders to combination IFN plus RBV (n = 219) or IFN monotherapy (n = 47), and relapsers to combination therapy (n = 55) were randomized to receive PEG IFN α-2b 1.5 μg/kg per wk plus RBV 800 mg per day (Regimen A, n = 160) or PEG IFN α-2b 1.0 μg/kg per wk plus RBV 1,000–1,200 mg per day (Regimen B, n = 161) for 48 wks.RESULTS:Sustained virologic response (SVR) occurred in 16% of the overall study population (Regimen A vs B, 18% vs 13%, p = 0.21), in 8% of the combination therapy nonresponders (10% vs 6%, p = 0.35), in 21% of the IFN monotherapy nonresponders (16% vs 27%, p = 0.35), and in 42% of the combination therapy relapsers (50% vs 32%, p = 0.18). In nonresponders to prior combination therapy, HCV ribonucleic acid levels <100,000 copies/mL at the end of the prior treatment course were associated with an increased SVR compared with levels ≥100,000 copies/mL (21% vs 5%, p = 0.002). In the overall study population, genotype 1 patients had lower SVR rates than others (14% vs 33%, p = 0.01), and African Americans had lower SVR than Caucasians (4% vs 18%, p = 0.01).CONCLUSION:Combination therapy with PEG IFN α-2b plus RBV is more effective in patients who relapsed after combination standard IFN plus RBV than in nonresponders to either combination therapy or IFN monotherapy. There was no significant effect of dosing regimen.

Pruritus in chronic hepatitis C: association with high serum bile acids, advanced pathology, and bile duct abnormalities.

Pruritus is a common symptom of chroniccholestatic liver diseases but is considered rare inchronic hepatitis. We observed pruritus to be anunusually common complaint in patients with advancedchronic hepatitis C. We reviewed the records of 175chronic hepatitis C patients to identify patients withsevere, diffuse, unexplained pruritus; 12 consecutiveprospective patients undergoing liver biopsy for chronic hepatitis C served as controls.Assessment included laboratory biochemical tests andassessment of liver pathology by stage, grade, hepaticactivity index, and a bile duct score. Pruritus waspresent in nine (5.1%) patients. Serum AST, ALT,alkaline phosphatase, GGTP, total bilirubin, andferritin were similar in pruritics and controls.Pruritics had higher serum bile acids (2028.4 ±223.1 mmol/liter vs 423.1 ± 194.3, P < 0.001), highertransferrin saturation (57.5 ± 6.8% vs 33.2± 3.3, P < 0.01), and lower HCV RNA by bDNA(24.5 ± 12.7 ± 10 vs 172.7 ± 54.1× 105, P < 0.05). Pathology revealedcirrhosis in 6/9 (66.6%) pruritics vs 1/12 (8.3%) controls (P < 0.01).Pruritics had higher pathologic stage (3.7 ± 0.2vs 2.2 ± 0.4, P < 0.01), grade (4.4 ±0.2 vs 2.1 ± 0.2, P < 0.001), activity index(14.3 ± 1.9 vs 8.6 ± 1.9, P < 0.025),and bile duct score (7.6 ± 0.6 vs 4.7 ± 0.4, P <0.01). Of eight pruritics treated withIFN-α2b, two had complete ALT responseand one relapsed. Pruritus followed a relapsing courseand only three patients partially responded despite a variety of interventions. Inconclusion, pruritus is a common complication ofadvanced CHC. Its presence is associated with high serumbile acids, advanced pathology and bile ductabnormalities. The clinical course of pruritus is relapsingand response to therapy is inconsistent. These featuressuggest that pruritus in CHC has a pathogenesis that mayvary from that of chronic cholestaticdiseases.

Interferon Alpha-2b and Ribavirin for Patients with Chronic Hepatitis C and Normal ALT

OBJECTIVES:Most studies establishing the role of antiviral therapy in patients with chronic hepatitis C (CHC) excluded the patients with normal ALT levels. Small trials with interferon monotherapy suggested a limited efficacy and/or de novo ALT elevations. We sought to evaluate the efficacy of two doses of interferon alpha-2b (IFN) with ribavirin (RBV) in patients with normal ALT.METHODS:Patients with biopsy-proven CHC with detectable HCV RNA and at least two normal ALT levels three or more months apart were randomized to receive either 3 or 5 million units of IFN thrice a week plus RBV 1,000–1,200 mg. Therapy was stopped at 24 wk if HCV RNA remained detectable and continued for an additional 24 wk if HCV RNA was undetectable. A final HCV RNA level was obtained 24 wk after discontinuation of therapy.RESULTS:Fifty-six patients were randomized and received at least one dose of treatment. The overall rate of sustained virologic response (SVR) was 32%. SVR rates were higher in genotype 2 and 3 patients (80%) than in genotype 1 patients (24%, p = 0.002). There was a tendency toward higher SVR in genotype 1 patients treated with the higher IFN dose (36% vs 10%, p = 0.07). Five patients had mild, transient ALT elevations. No sustained ALT elevations were noted.CONCLUSIONS:Patients with normal ALT had a rate of SVR comparable to that reported in patients with elevated ALT. Higher dose of interferon tended to be more effective in genotype 1 infected patients. De novo ALT elevations were transient and not clinically significant. Patients with CHC should not be excluded from treatment on the basis of ALT alone. Combination therapy with pegylated interferon and ribavirin should be evaluated in these patients.

Effect on treatment outcome of coinfection with SEN viruses in patients with hepatitis C.

The newly discovered SEN D and SEN H viruses are transmitted parenterally and can cause post-transfusion hepatitis. We assessed whether coinfection of patients with chronic hepatitis C and SEN D or SEN H correlates with the outcome of treatment with interferon and ribavirin. Of 31 patients with hepatitis C studied, six were positive for SEN D and seven for SEN H (one was positive for both). All of those positive for SEN D and five of those positive for SEN H failed to respond to therapy. Overall response (RNA titre and alanine aminotransferase concentration after treatment) was lower in SEN-infected patients than uninfected patients (p=0.025). We conclude that coinfection with SEN viruses is frequent in chronic hepatitis C patients and might adversely affect the outcome of treatment with interferon and ribavirin.

Fructose Mediated Non-Alcoholic Fatty Liver Is Attenuated by HO-1-SIRT1 Module in Murine Hepatocytes and Mice Fed a High Fructose Diet

Background Oxidative stress underlies the etiopathogenesis of nonalcoholic fatty liver disease (NAFLD), obesity and cardiovascular disease (CVD). Heme Oxygenase-1 (HO-1) is a potent endogenous antioxidant gene that plays a key role in decreasing oxidative stress. Sirtuin1 (SIRT1) belongs to the family of NAD-dependent de-acyetylases and is modulated by cellular redox. Hypothesis We hypothesize that fructose-induced obesity creates an inflammatory and oxidative environment conducive to the development of NAFLD and metabolic syndrome. The aim of this study is to determine whether HO-1 acts through SIRT1 to form a functional module within hepatocytes to attenuate steatohepatitis, hepatic fibrosis and cardiovascular dysfunction. Methods and Results We examined the effect of fructose, on hepatocyte lipid accumulation and fibrosis in murine hepatocytes and in mice fed a high fructose diet in the presence and absence of CoPP, an inducer of HO-1, and SnMP, an inhibitor of HO activity. Fructose increased oxidative stress markers and decreased HO-1 and SIRT1 levels in hepatocytes (p<0.05). Further fructose supplementation increased FAS, PPARα, pAMPK and triglycerides levels; CoPP negated this increase. Concurrent treatment with CoPP and SIRT1 siRNA in hepatocytes increased FAS, PPARα, pAMPK and triglycerides levels suggesting that HO-1 is upstream of SIRT1 and suppression of SIRT1 attenuates the beneficial effects of HO-1. A high fructose diet increased insulin resistance, blood pressure, markers of oxidative stress and lipogenesis along with fibrotic markers in mice (p<0.05). Increased levels of HO-1 increased SIRT1 levels and ameliorated fructose-mediated lipid accumulation and fibrosis in liver along with decreasing vascular dysfunction (p<0.05 vs. fructose). These beneficial effects of CoPP were reversed by SnMP. Conclusion Taken together, our study demonstrates, for the first time, that HO-1 induction attenuates fructose-induced hepatic lipid deposition, prevents the development of hepatic fibrosis and abates NAFLD-associated vascular dysfunction; effects that are mediated by activation of SIRT1 gene expression.

Efficacy of high-dose interferon in combination with ribavirin in patients with chronic hepatitis C resistant to interferon alone.

OBJECTIVE:Interferon combined with ribavirin has efficacy in the treatment of patients with chronic hepatitis C virus (HCV) infection. However, its utility in patients who have not responded to prior interferon therapy is not clear. Furthermore, the effect of using an increased dose of interferon in combination with ribavirin in patients with chronic hepatitis C resistant to conventional doses of interferon is not known. The aim of our study was to evaluate the effect of high-dose interferon in combination with ribavirin on the efficacy of treating patients with chronic hepatitis C resistant to interferon monotherapy in a large multicenter trial.METHODS:We randomized 154 patients with chronic hepatitis C who failed to achieve a sustained response with prior interferon therapy to receive either 3 or 5 MU of interferon α-2b and ribavirin (1000–1200 mg/day) for 12 months. There were 119 patients who had not responded and 35 who initially responded but relapsed after prior interferon monotherapy. Serum HCV RNA levels were measured at entry, 6, and 12 months of treatment and at the end of a 6-month follow-up period.RESULTS:The mean age of the subjects was 47 yr (range 28–68 yr), and 110 (71.4%) were men. One hundred thirty-two patients (86%) had HCV genotype 1, whereas 21(14%) had cirrhosis. Eighty-one subjects (53%) were randomized to receive 3 MU of interferon α-2b. Fifteen of 35 relapse subjects (43%) and 12 of 119 prior nonresponder entrants (10%) achieved a sustained virological response to the 12-month course of treatment. Overall, 11 of 81 patients (14%) receiving 3 MU, and 16 of 73 patients (22%) receiving 5 MU of interferon maintained an undetectable HCV RNA level after cessation of therapy. The difference in sustained response rates between the two interferon dosage groups did not reach statistical significance (p = 0.09). However, among the nonresponder patients alone, there was an increased sustained response in the high-dose interferon group compared with the standard interferon dose group (15.5% vs 4.9%, p = 0.055). Twenty-six patients discontinued therapy before 6 months, including 10 patients (12.3%) in the 3-MU and 16 patients (21.9%) in the 5-MU groups (p = 0.17).Conclusions:Sustained virological response to combined interferon α-2b and ribavirin was significantly higher in relapse patients than those who did not respond to prior interferon monotherapy. Although, when all treated patients were analyzed, there was no significant difference in sustained response between subjects receiving 3 and 5 MU of interferon, among the prior nonresponder patients, treatment with 5 MU of interferon with ribavirin resulted in a slightly increased response compared with treatment with the standard interferon dosage. The tolerability of the treatment regimens was comparable.

Non-alcoholic fatty liver disease (NAFLD): why you should care, when you should worry, what you should do

For the diabetologist, non‐alcoholic fatty liver disease (NAFLD) is important at both ends of its spectrum. It is an early warning sign of future risk of metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease. It may also lead to late life‐threatening sequela of diabetes mellitus in the event of progression to liver failure or hepatocellular carcinoma. This review will highlight the recent progress in understanding the natural history of non‐alcoholic fatty liver disease and in developing a rational approach to its diagnosis, staging, and management. The pandemic prevalence of non‐alcoholic fatty liver disease in Western countries necessitates both a high index of suspicion to identify cases and a non‐invasive approach to staging, which is best achieved with clinical/biochemical panels and transient elastography. Lifestyle modification is the cornerstone of management. Recent clinical trials provide support for pharmacologic therapies directed at the metabolic syndrome and at protecting the liver but more data are needed. Bariatric surgery is appropriate for high‐risk patients who fail conservative management. Patients with liver failure or hepatocellular carcinoma may be candidates for liver transplantation. Copyright

Cardiovascular considerations in patients undergoing gastrointestinal endoscopy.

Gastrointestinal endoscopies are common procedures for diagnosis and treatment. Patients with various cardiovascular conditions can undergo these procedures, including those patients with acute myocardial infarction, but appropriate precautions need to be maintained, especially with procedure-induced autonomic nervous system pertubations that can affect heart rate and blood pressure. In this article, treatment recommendations are included for those patients undergoing endoscopy who are receiving anticoagulation and for those who are at risk for bacterial endocarditis.

Upper gastrointestinal bleeding following open heart surgery. Predominant finding of aggressive duodenal ulcer disease.

We reviewed our experience with endoscopically evaluated severe upper gastrointestinal hemorrhage following open heart surgery. Of 4892 patients undergoing open heart surgery, 18 (0.4%) sustained upper gastrointestinal hemorrhage requiring endoscopic evaluation. Endoscopy identified the source of bleeding in all cases. No significant complications of endoscopy were observed. Duodenal ulcers (DUs) were found in 16 (89%) of cases and were felt to be the source of bleeding in 15 (83%). Aggressive features, such as multiplicity, large size, or distal location were associated with 13 (81%) of the DU cases. Complications necessitated endoscopic or surgical therapy in eight (44%) patients with DUs. We conclude that aggressive DU disease accounts for the majority of severe upper gastrointestinal bleeding following open heart surgery.

Potentiation of Acetaminophen Hepatotoxicity by Phenytoin, Leading to Liver Transplantation

We report the case of a 22-year-old man who developed fulminant hepatic failure 3 days after an intentional acetaminophen overdose. The patient had a history of a seizure disorder for which he was taking phenytoin. The acetaminophen level at presentation was in the “nontoxic” range. Emergent liver transplantation was performed 4 days after the ingestion. This is the first reported case of successful liver transplantation for acetaminophen-induced fulminant hepatic failure in the setting of phenytoin therapy.