Hepatitis C Treatment And Liver Transplantation: An Update 2011

Advances in Chronic Hepatitis C Treatment And Liver Transplantation: An Update
The Center for the Study of Hepatitis C (CSHC) at NewYork-Presbyterian/Weill Cornell Medical Center is engaged in diverse HCV investigations. One of us (Dr. Talal) has undertaken research on viral kinetics, presenting the first evaluation of pegIFN pharmacokinetics in patients coinfected with HCV and HIV, finding that, although pharmacokinetic parameters do not differentiate sustained virological responders from nonresponders, certain pharmaco - dynamic measurements do and might therefore serve as useful predictors of treatment outcome.
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Spotting Gene Variants May Boost Hepatitis C Treatment
(also see NATAP)
Research zeroes in on patients with protection from drug-induced anemia
WEDNESDAY, Jan. 26 (HealthDay News) -- Scientists have pinpointed two gene variants that protect hepatitis C patients from anemia caused by antiviral treatment.
The findings are detailed in two studies that appear online and in the February print issue of the journal Hepatology.

The ability to identify patients with the two variants in the inosine triphosphatase (ITPA) gene will help ensure that antiviral therapy is completed and the hepatitis C virus (HCV) is eliminated, the researchers say in a news release from the journal's publisher.
Up to 170 million people worldwide have chronic HCV infection, which is a leading cause of end-stage liver disease. HCV is curable with the antiviral drugs pegylated interferon and ribavirin, but these medications cause anemia in many patients.

In one study, Italian researchers looked at 238 HCV patients treated with the antiviral drugs and found that the two ITPA variants were strongly associated with protection from anemia.
Japanese scientists found similar results in their study of 61 patients with HCV.

From NATAP

Gene Variants Linked to Hepatitis C Treatment-Related Anemia Identified -
"In conclusion, genetic polymorphisms in the ITPA gene were associated with protection from RBV-associated anemia in patients being treated with a short course of PEG-IFN plus high-dose RBV (1000/1200 mg daily) for genotype 2/3 HCV. In this cohort, however, ITPA variants were not associated with the need for RBV dose modification or treatment outcome, despite a median RBV dose of 15 mg/kg. The clinical utility of ITPA genotyping in the setting of genotype 2/3 HCV, therefore, remains unclear, particularly for treatment protocols in which 800 mg of RBV is used daily. It may find a role in the pretreatment assessment of patients at high risk for RBV-associated anemia or related morbidity." Mangia Hepatology full-text, pdfs to follow......

Inosine triphosphatase genetic variants are protective against anemia during antiviral therapy for HCV2/3 but do not decrease dose reductions of RBV or increase SVR - pdf attached -
We recently identified strong and independent associations between two functional variants in the inosine triphosphatase (ITPA) gene on chromosome 20 that caused an inosine triphosphatase (ITPase) deficiency5-8 and protection from early RBV-induced hemolytic anemia in genotype 1 HCV-infected patients enrolled in the Individualized Dosing Efficacy Versus Flat Dosing to Assess Optimal Pegylated Interferon Therapy trial.9, 10 In a follow-up study of genotype 1 HCV-infected patients from the Viral Resistance to Antiviral Therapy of Chronic Hepatitis C study, the ITPA variants protected against anemia throughout 48 weeks of therapy and were associated with a lesser frequency of RBV dose reduction.11ITPA variants were not significantly associated with virological treatment outcome in either study.

Influence of ITPA polymorphisms on decreases of hemoglobin during treatment with pegylated interferon, ribavirin, and telaprevir - pdf attached
Patients infected with HCV-1 carrying the CC genotype at rs1127354 are more prone to develop anemia than those with CA/AA genotypes during the combination therapy, and the decrease in hemoglobin is greater in patients with the AA than AC/CC genotypes at rs7270101.7 Their observations have been extended to many patients in a large-scale trial with pegIFN-α-2a on Caucasian and African Americans,12 as well as in the Japanese receiving PEG-IFN-α-2b and RBV who were infected with HCV-1.13


Fatty Liver

Histologic Benefit of Vitamin E in NASH
Occurs Independently of Changes in Insulin Resistance
Mechanisms Behind Benefit of Vitamin E in Patients With NASH Still Unclear

David Wild
San Antonio—Patients treated for nonalcoholic steatohepatitis (NASH) with vitamin E or pioglitazone may experience histologic improvements without showing improvements in an index of adipose tissue insulin resistance (Adipo-IR), according to data presented at the 2010 American College of Gastroenterology annual meeting (Zein C et al. Am J Gastroenterol 2010;105[suppl 1]:S114. Abstract 308). The study investigators reported that patients who received vitamin E showed improvements in liver histology despite worsening of adipose tissue insulin resistance.

“Based on these results, we need to look for another mechanism of action to explain the efficacy of vitamin E for treating NASH,” commented Alan Cutler, MD, clinical associate professor of medicine at Wayne State University in Detroit, who was not involved in the study.

The new findings were based on data from the PIVENS (Pioglitazone vs. Vitamin E vs. Placebo for the Treatment of Non-Diabetic Patients with Nonalcoholic Steatohepatitis) trial, which was published last year in The New England Journal of Medicine (Sanyal AJ et al. 2010;362:1675-1685). In the current analysis of this placebo-controlled trial, lead investigator Lauren Bell, PhD, assistant research professor in the Department of Gastroenterology and Hepatology at Indiana University School of Medicine in Indianapolis, and colleagues investigated whether changes in adipose tissue insulin resistance are responsible for the improvement in liver histology seen with vitamin E. In the PIVENS trial, 246 patients with NASH who did not have diabetes were randomized to receive 30 mg pioglitazone (n=80), 800 international units vitamin E (n=84) or placebo (n=82) for 96 weeks. Dr. Bell’s team analyzed fasting serum nonesterified fatty acid levels and insulin concentrations, which both serve as a composite index of Adipo-IR, and compared these Adipo-IR values with histologic changes observed in the three groups.
Subjects who received vitamin E showed statistically significant improvements in hepatic histology, whereas those on pioglitazone showed favorable, but nonsignificant, histologic outcomes.

The investigators found no significant differences in median Adipo-IR index scores between the three groups at baseline. After 96 weeks, median Adipo-IR index scores among those who received vitamin E rose from 39.7 to 48.8, whereas median Adipo-IR index scores for those in the pioglitazone group dropped from 44.5 to 34.5. Adipo-IR values among the two treatment groups at 96 weeks were not significantly different from each other or from those in the placebo group.

Although these findings suggest no clear correlation between aggregate measures of Adipo-IR and NASH-related histologic changes, further statistical analyses revealed decreases in Adipo-IR index scores correlated significantly with decreases in steatosis grade and nonalcoholic fatty liver disease activity scores, and increases in Adipo-IR index scores were correlated with increases in fibrosis scores (P≤0.05 for all). Thus, Dr. Bell believes that this last set of findings suggests Adipo-IR may be a proxy measure of histologic changes in this group of patients.
“If future studies confirm these associations, changes in Adipo-IR index scores may serve as a useful noninvasive marker of changes in NASH-related steatosis and fibrosis,” Dr. Bell said.


Pentoxifylline Improves Liver Histology in Patients With NASH
David Wild

San Antonio–Pentoxifylline, a tumor necrosis factor (TNF)-α inhibitor, significantly improved histologic features in 50% of people with nonalcoholic steatohepatitis (NASH) compared with 16% of patients who improved on placebo, according to a study presented at the 2010 American College of Gastroenterology annual meeting (Zein C et al. Am J Gastroenterol 2010;105[suppl 1]:S114. Abstract 308).

“These results are particularly encouraging in light of the paucity of effective medical therapeutic agents for NASH,” said lead investigator Claudia Zein, MD, assistant professor in the Department of Gastroenterology and Hepatology at Cleveland Clinic, in Ohio.
Although pentoxifylline was more effective than placebo in this study, Mitchell Shiffman, MD, director of the Liver Institute of Virginia, a part of the Bon Secours Hampton Roads Health System in Newport News, asserted that the associated improvements were mild. He also suggested that new NASH treatments should be measured against the current gold standard in NASH treatment.

“In light of the effectiveness of vitamin E, it is no longer reasonable to compare new NASH treatments to placebo. Any new treatment should be compared with vitamin E,” maintained Dr. Shiffman, who was not involved in the study.

To determine the efficacy of pentoxifylline for treating NASH, Dr. Zein and colleagues at two tertiary treatment centers recruited 55 adults with biopsy-confirmed NASH and randomly assigned 26 patients to receive 400 mg pentoxifylline three times daily for one year and 29 participants to receive a placebo three times daily for the same duration. The patients had similar demographic characteristics at baseline and also had similar mean values—5.7 for pentoxifylline subjects and 5.4 for placebo participants—on the nonalcoholic fatty liver disease activity score (NAS), a composite measure of steatosis, lobular inflammation and hepatocellular ballooning.

The investigators observed that 38.5% of patients receiving pentoxifylline—including those who did not complete the study—experienced a decrease of at least two points on the NAS one year after baseline compared with 13.8% of those on placebo (P=0.036). The frequency of treatment-related improvements was greater when the researchers only included study completers, with 50% of the pentoxifylline group exhibiting a decrease of at least two points on the NAS compared to 16% of the placebo group (P=0.01). Average NAS values dropped a mean 1.5 points in the pentoxifylline group after one year compared with 0.2 points in the placebo group (P<0.001). p="0.02)." href="http://www.gastroendonews.com/index.asp?show=currissue">http://www.gastroendonews.com/index.asp?show=currissue