Faculty Bibliography

In nonalcoholic steatohepatitis (NASH), extent of hepatocyte apoptosis correlates with disease severity. Reducing hepatocyte apoptosis with the selective caspase inhibitor GS-9450 has a potential for altering the course of the liver disease. In this phase 2, double-blind study, 124 subjects with biopsy-proven NASH were randomized to once-daily placebo or 1, 5, 10, or 40 mg GS-9450 for 4 weeks. Absolute and percent changes from baseline in ALT levels, AST levels, and caspase 3-cleaved cytokeratin (CK)-18 fragments at Week 4 were assessed by an analysis of covariance model with adjustment for baseline values. In the 40-mg group, mean (SD) ALT decreased by 47 (43) U/L from baseline to Week 4 (P < 0.0001 versus placebo), and the proportion of subjects with normal ALT increased from 0% to 35% at Week 4. In the 40-mg group, mean AST decreased by 13 U/L from baseline (not significant), and the proportion with normal AST increased from 20% at baseline to 48% at Week 4. By Week 4, mean CK-18 fragments decreased 393 (723) U/L in the GS-9450 10-mg group and 125 (212) U/L in the 40-mg group, but these reductions were not statistically significant. No serious adverse events were reported during treatment, and the percentage of subjects with at least one treatment-emergent Grade 3 or 4 laboratory abnormality ranged from 11.5% to 17% across the GS-9450 treatment groups versus 35% in the placebo group. Conclusions. GS-9450 treatment induced significant reductions in ALT levels in NASH patients. Reductions in CK-18 fragments also occurred, although they were not statistically significant. At appropriate therapeutic indices, selective caspase inhibitors may be a promising treatment option in patients with NASH. (HEPATOLOGY 2011.)

Treating patients with the hepatitis C virus (HCV) is about to be changed forever. Over 170 million people are infected with HCV worldwide and this number grows as more and more patients are diagnosed with hepatitis C daily. Current standard of care (SoC) treatment for chronic hepatitis C consists of pegylated interferon (Peg IFN) and ribavirin (RBV). Success rates for viral eradication-sustained virological response (SVR), for patients infected with HCV genotype 1 (G1), the most common HCV genotype in the United States are less than 50%. New drugs, known as direct acting antivirals (DAAs), have been in development for over a decade, and the initial two of these, boceprevir and telaprevir, both protease inhibitors, have just been FDA approved (May 2011). Treating HCV with the addition of protease inhibitors to SoC is very promising with SVRs of approximately 70-75% in recent studies. This article, the first in this series, will review the burden of hepatitis C, the HCV lifecycle, and the studies behind the new therapies in an effort to preview how patients will likely be treated in the near future

Background: Adherence to pegylated interferon (PIFN) plus ribavirin (RBV), especially in the first 12 weeks, affects sustained virologic response (SVR) in patients with chronic hepatitis C virus (HCV). RibaPak (RBP) requires fewer tablets than RBV. Aim: To determine if simplifying the dosing regimen of RBV impacts outcomes. Methods: Ninety-two patients on RBP >12 weeks were categorized as follows: Group A (n = 22): treatment experienced with IFN/PIFN and RBV, Group B (n = 49): treatment naive switched to RBP after >12 weeks RBV, Group C (n = 21): treatment naive on RBP. Outcomes were compared between RBP and RBV in Groups A and B. Group C was compared to Group D - a matched control group of RBV-treated patients. Results: Patients preferred RBP. RBP was associated with improved patient compliance, less side effects, improved quality of life and a trend toward improved SVR. Conclusions: RibaPak offers an attractive alternative to RBV