November 22, 2010

The efficacy and safety of pegylated interferon plus ribavirin combination therapy in chronic hepatitis c patients with hepatocellular carcinoma post curative therapies - A multicenter prospective trial

J Hepatol. 2010 Sep 7. [Epub ahead of print]

Huang JF, Yu ML, Huang CF, Chiu CF, Dai CY, Huang CI, Yeh ML, Yang JF, Hsieh MY, Hou NJ, Lin ZY, Chen SC, Wang LY, Chuang WL.

Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.


BACKGROUND & AIMS: Evidence on the efficacy of antiviral treatment in chronic hepatitis C (CHC) patients with hepatocellular carcinoma (HCC) after curative treatment is scarce. We aimed to evaluate the efficacy and safety of pegylated interferon-alpha plus ribavirin (pegIFN/RBV) combination therapy in these patients, compared to cirrhotic patients.

METHODS: This prospective, multicenter, case-control study recruited 82 consecutive CHC patients with HCC after curative management and 87 sex/age-matched cirrhotic patients. All patients received pegIFN-alpha-2a and weight-based RBV according to current treatment recommendations. The primary outcome measurement was sustained virological response (SVR, seronegative of hepatitis C virus RNA throughout the 6-month post-treatment follow-up period).

RESULTS: The SVR rate was significantly lower in the HCC group compared to the cirrhosis group (48.8% vs 64.4%, p=0.04). However, the significantly lower rate of SVR in the HCC group was observed among genotype-1 patients (33.3% vs 60.7%, p=0.005) but not among genotype-2/3 patients (70.6% vs 71.0%, p=0.88). In patients who achieved 80/80/80 adherence, there was no significant difference of SVR rate between groups (50.7% vs 64.2%, p=0.12) Multivariate logistic regression analysis demonstrated that rapid virological response (viral clearance during the first 4weeks of treatment, odds ratio=22.1, p<0.001) and adherence (odds ratio=3.1, p=0.05) were predictive factors associated with SVR, whilst previous occurrence of HCC was not associated with SVR (Odds ratio=0.4, p=0.09). The incidence of severe adverse events did not differ between the two groups.

CONCLUSIONS: The study proved the feasibility of pegIFN/RBV therapy with current treatment guidelines in CHC patients after successful eradication of HCC, with careful monitoring.

Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

PMID: 21056500 [PubMed - as supplied by publisher]


Association of host pharmacodynamic effects with virologic response to pegylated interferon alfa-2a/ribavirin in chronic hepatitis C

Hepatology. 2010 Aug 31:1907-1915. [Epub ahead of print]

Chung RT, Poordad FF, Hassanein T, Zhou X, Lentz E, Prabhakar A, Di Bisceglie AM.

From Massachusetts General Hospital, Boston, MA.


Patients receiving therapy for chronic hepatitis C virus (HCV) infection frequently experience cytopenias and weight loss. We retrospectively assessed the pharmacodynamic effects of pegylated interferon (PEG-IFN) alfa-2a and ribavirin by evaluating the relationship between changes in hematologic parameters, body weight, and virologic response. Patients with HCV genotypes 1, 4, 5, or 6 receiving 24 or 48 weeks of PEG-IFN alfa-2a and ribavirin therapy were pooled from four phase 3/4 trials. Maximum decreases in hemoglobin level, neutrophil count, platelet count, and weight during therapy were assessed according to virologic response category (sustained virologic response [SVR], relapse, breakthrough, and nonresponder) and race/ethnicity. Of 1,778 patients analyzed, more than half were male, non-Hispanic Caucasian, and infected with HCV genotype 1; had a baseline HCV RNA >800,000; and had alanine aminotransferase levels ≤3 × the upper limit of normal. Virologic responders (SVR, relapse, and breakthrough) experienced greater maximum decreases from baseline in hemoglobin level, neutrophil count, platelet count, and weight compared with nonresponders; however, no clear trend was observed between SVR, relapse, and breakthrough. After adjusting for drug exposure and treatment duration, only decreases in neutrophil count remained associated with virologic response. Significantly greater declines in neutrophil (P < 0.0001) and platelet (P < 0.005) count were observed at weeks 4, 12, and 24 of therapy in virologic responders compared with nonresponders. This difference between responders and nonresponders was also observed among racial/ethnic groups, although statistical significance was not consistent across all groups. Conclusion: This post hoc analysis of HCV patients treated with PEG-IFN alfa-2a and ribavirin shows that maximum decreases from baseline in hematologic parameters and weight loss were associated with virologic response. However, after adjusting for drug exposure and accounting for duration of therapy, only neutropenia was independently associated with virologic response. (HEPATOLOGY 2010;).

PMID: 21064034 [PubMed - as supplied by publisher]


Uptake and delivery of hepatitis C treatment in opiate substitution treatment: perceptions of clients and health professionals

J Viral Hepat. 2010 Dec;17(12):839-44. doi: 10.1111/j.1365-2893.2009.01250.x.

Treloar C, Newland J, Rance J, Hopwood M.

National Centre in HIV Social Research, The University of New South Wales, Sydney, NSW, Australia.


Summary.  Uptake of treatment for hepatitis C virus (HCV) infection is very low particularly among people who have injected drugs. Opiate substitution treatment (OST) programs, with a high prevalence of people living with HCV, have been a site of growing interest in the delivery of hepatitis C treatment. There has been no exploration of OST clients' and health professionals' perceptions of the barriers and facilitators to uptake and delivery of HCV treatment in OST clinics from personal and organizational perspectives. This qualitative study involved interviews with 27 OST clients in New South Wales and a focus group and interviews with 22 Australian OST health professionals. Clients and health professionals viewed hepatitis C treatment in OST as a 'one-stop-shop' model which could increase access to and uptake of treatment and build on existing relationships of trust between OST client and health professional. Elements of the organizational culture were also noted as barriers to HCV treatment delivery including concerns about confidentiality, lack of discussion of HCV treatment and that HCV treatment was not perceived by clinicians as a legitimate activity of OST clinics. OST client participants also reported a number of personal barriers to engaging with HCV treatment including family responsibilities (and concerns about treatment side effects), unstable housing, comorbidities and perceptions of the unsatisfactory level of treatment efficacy. These findings emphasize the need for future research and delivery of services which addresses the complexity of care and treatment for people in marginalized social circumstances.

© 2010 Blackwell Publishing Ltd.

PMID: 20070504 [PubMed - in process]


Typical acetaminophen dose no threat to kids' livers

By Frederik Joelving
Mon Nov 22, 2010 4:02am EST

NEW YORK (Reuters Health) - Concerns about liver injuries in kids who take the common painkiller acetaminophen -- sold as Tylenol in the U.S. -- are unfounded, researchers said on Monday.

"None of the 32,000 children in this study were reported to have symptoms of obvious liver disease," said Dr. Eric Lavonas of the Rocky Mountain Poison and Drug Center in Denver. "The only hint of harm we found was some lab abnormalities."

With more than eight million American kids taking the drug every week, acetaminophen is the nation's most popular drug in children.

It's toxic to the liver in high doses, and can be fatal if taken in excess. Very rarely, adults may also get liver damage at normal doses, so doctors had worried if the same was true for kids.

"This drug is used so commonly that even a very rare safety concern is a big concern," said Lavonas, whose findings appear in the journal Pediatrics.

Some researchers suspect there is a link between long-term use of acetaminophen and the global rise in asthma and allergies, but the evidence is far from clear at this point.

For the new report, researchers pooled earlier studies that followed kids who had been given acetaminophen for at least 24 hours.

There were no reports of liver injuries leading to symptoms -- stomachache, nausea or vomiting, for instance -- in the 62 reports they found.

Ten kids, or about three in 10,000, had high levels of liver enzymes in their blood, which usually means their livers have been damaged.

In most cases, however, those elevations were unrelated to acetaminophen. And even if they were caused by the drug, they don't indicate lasting damage, according to Lavonas.

"Acetaminophen is extremely safe for children when given correctly," he said. "Parents should not be afraid to give acetaminophen to their children when they need it, but they should be very careful about giving the right dose."

"If you suspect that you have given a child an overdose, call your state's poison center," he added.

The Rocky Mountain Poison and Drug Center receives funding from McNeil Consumer Healthcare, the Johnson & Johnson subsidiary that sells Tylenol, but the researchers said the company did not support this study.

SOURCE: Pediatrics, online November 22, 2010.


Biolex reveals ePRO surprise; selection process

November 22, 2010 — 1:32am ET
By George Miller

Biolex CEO Jan Turek notes something unforeseen in the ePRO element of the company's recent trial of a hepatitis C treatment: The degree of difference in reports of side-effect severity in the weekly case report forms completed by clinicians versus the daily ePRO accounts of trial volunteers. Some 85 percent of reports by doctors describe mild side-effects, whereas the volunteers reporting electronically most often rated the severity as moderate or severe.

It was "a surprise to us and our key opinion leaders," Turek says in a phone interview. "It brought home the need for patient reports to be taken more seriously."

Findings from the trial do, however, reflect commonality between the reporting media types in the trial's side-effect result--a statistically significant 40 to 50 percent drop in the frequency and severity of flu-like symptoms for the 480-microgram dose of Biolex's Locteron compared with the PEG-Intron control.

Researchers were tracking the flu-like symptoms as a means of comparing the treatments in the Phase IIb trial. "What you measure drives how you gather data," explains Biolex CFO Dale Sander in the interview. Investigators as well as the key opinion leaders thought ePRO fit the bill. The side-effect data collected through the ePRO system are considered supplemental to the reports taken during weekly clinic visits.

Biolex used an ePRO system from Unithink in the global trial. Among the key factors in its choice was the system's ability to instantaneously receive reports and capture them in the EDC system, rather than a set-up that involves reporting and later docking and uploading, says Amy Rigney, clinical ops director. "That was a differentiator."

Another was ease of patient use. "We wanted to be sure the ePRO system was programmed for several languages." Also, ePRO/EDC set-up allowed trial volunteers to report side effects via cellphone or laptop. "It didn't force the issue one way or the other," she says.

Biolex evaluated available ePRO systems in 2008 and had several months of discussions involving investigators, the data management group, and the clinical group. The company's IT team participated throughout the process to ensure overall systems compatibility, says Rigney, including the final selection of Unithink.

"Volunteers' recall and ability to assess a side effect is better when they are entering the data simultaneous with the event," she says. "You're getting it unfiltered."


Smoking and severity of hepatic fibrosis in nonalcoholic fatty liver disease☆

Articles in Press

Claudia O. Zein 12, Aynur Unalp 3, Ryan Colvin 3, Yao-Chang Liu 2, Arthur J. McCullough 12, for the Nonalcoholic Steatohepatitis Clinical Research Network

Received 22 March 2010; received in revised form 8 July 2010; accepted 16 July 2010. published online 18 November 2010.
Uncorrected Proof

Background & Aims
Although many predictors of disease severity of nonalcoholic fatty liver disease (NAFLD) have been proposed, studies of the potential effects of specific environmental exposures on human NAFLD are lacking. Smoking increases insulin resistance. Given the pathophysiological role of insulin resistance in NAFLD, characterization of the influence of smoking in NAFLD is warranted. The aim of this paper was to study the potential association between cigarette smoking and advanced fibrosis in NAFLD.

All adults enrolled in the NASH CRN studies between October 2004 and February 2008 who had liver biopsies were included (n=1091). Advanced fibrosis was defined as stages 3–4. Analyses were performed.

Significant bivariate associations were demonstrated between advanced fibrosis and age, gender, ethnicity, diabetes, and smoking history. History of smoking 10 pack-years was more common (p<0.0001) among patients with advanced fibrosis. Multivariate analysis demonstrated an association between smoking history of 10 pack-years and advanced fibrosis (OR=1.63). Among non-diabetics, history of 10 pack-years was associated with an OR of 2.48 for advanced fibrosis. High frequencies of advanced fibrosis were observed among diabetics (with or without 10 pack-years history) and non-diabetics with 10 pack-years history as compared to non-diabetics without significant smoking history.

Smoking history was associated with advanced liver fibrosis in this large multicenter cohort of NAFLD patients. The results indicate that smoking may enhance the progression of NAFLD partly through its effect on insulin resistance. Our results are consistent with recent animal studies suggesting that cigarette smoke may aggravate fatty liver. To our knowledge, this is the first study to show that cigarette smoking is associated with increased fibrosis severity in human NALFD, suggesting it may accelerate disease progression. These results may support a formal recommendation of smoking cessation in patients with NAFLD.

Abbreviations: NAFLD, nonalcoholic fatty liver disease, NASH CRN, nonalcoholic steatohepatitis clinical research network, DM, type 2 diabetes mellitus, BMI, body mass index, SD, standard deviation, OR, odds ratio

Keywords: Smoking, Alcohol, Nonalcoholic fatty liver disease, Liver fibrosis, Predictors

1 Cleveland Clinic, Cleveland, OH, USA
2 Case Western Reserve University, Cleveland, OH, USA
3 Johns Hopkins University, Baltimore, MD, USA

Corresponding author at: Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44915, USA.

☆ This work was presented, in part, at the Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), November 2007, Boston, MA.

PII: S0168-8278(10)00833-0
© 2010 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.


Low-dose peginterferon alfa-2a (40KD) is safe and produces a SVR in Patients with chronic hepatitis C and End-Stage Renal Disease

Clin Gastroenterol Hepatol. 2010 Nov 4. [Epub ahead of print]

Peck-Radosavljevic M, Boletis J, Besisik F, Ferraz ML, Alric L, Samuel D, Messinger D, Tietz A, Cheinquer H.

University of Vienna, Vienna, Austria.


BACKGROUND & AIMS: Chronic hepatitis C increases mortality of patients with end-stage renal disease (ESRD). Ribavirin is not recommended for patients with renal dysfunction; peginterferon monotherapy is the most appropriate treatment for chronic hepatitis C in such patients. We evaluated the efficacy and safety of 2 dosages of peginterferon alfa-2a (40KD) in patients with chronic hepatitis C and ESRD on hemodialysis.

METHODS: We performed a randomized, multi-centre, open-label clinical study of 85 patients with chronic hepatitis C and ESRD who were receiving hemodialysis at specialist outpatient hepatology clinics. Patients were treated with subcutaneous peginterferon alfa-2a (40KD) at dosages of 135 or 90 μg/week for 48 weeks.

RESULTS: The incidence of overall sustained virologic responses (SVR, undetectable hepatitis C virus [HCV] RNA [<50 IU/mL] after 24 weeks of untreated follow-up) were 39.5% (15/38) in the 135 μg/week group and 34.9% (15/43) in the 90 μg/week group (odds ratio: 1.22; 95% confidence interval: 0.49-3.06; P=0.6746). Among patients with undetectable HCV RNA at week 12, 60.9% (14/23) of those in the 135 μg/week and 87.5% (14/16) of those in the 90 μg/week group achieved an SVR. Therapy was well tolerated with no new safety concerns. The most common adverse events (>10% of patients in at least 1 treatment group) included conditions associated with ESRD (anemia and hypertension) and with interferon treatment.

CONCLUSIONS: Forty-eight weeks of treatment with low-dose peginterferon alfa-2a (40KD) is safe and produces an SVR in 35%-40% of patients with chronic hepatitis C and ESRD on hemodialysis.

Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

PMID: 21056689 [PubMed - as supplied by publisher]