Faculty Bibliography

Chronic hepatitis C virus (HCV) infection is a pressing medical problem worldwide. Current therapy with pegylated interferon plus ribavirin (Peg-IFN/RBV) is associated with a poor risk benefit profile, a long treatment duration (48 weeks) and inadequate success rate (approximately 40-50%) of SVR (sustained viral response) in patients infected with genotype 1 HCV. This review is focused on recent clinical trial results with specifically targeted antiviral therapy for HCV (STAT-C) protease and polymerase inhibitors. In the past decade, anti-HCV drug discovery has focused first on targeting host factors required for viral replication and second on multiple HCV antiviral agents. Owing to the large number of HCV inhibitors currently in pre-clinical and clinical development today, we have focused on the most advanced compounds in the HCV polymerase and HCV protease inhibitor classes. Within each class, compounds will be used to illustrate some of the properties associated with inhibitors that bind to the active site of HCV polymerase, the active site of HCV protease (macrocyclic and linear ketoamide inhibitors) and allosteric polymerase inhibitors.

Chronic hepatitis C affects 170 million people worldwide, including up to 4 million people in the United States. The current standard of care therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV) while highly successful in patients with genotype 2 and 3 infection, allows for sustained virologic response in 42-46% of treatment-naive genotype 1 patients, comprising about 70% of cases of chronic hepatitis C in the USA. While awaiting approval of Specifically Targeted Antiviral Therapy for HCV (STAT-C) agents, which will require the completion of additional clinical trials, it is important to optimize the dose and duration of currently available treatment modalities, namely PEG-IFN and RBV, for treatment of CHC. Results of several recent trials evaluating optimal dosing of RBV and higher than standard dosing of PEG-IFN in treatment-naive genotype 1 patients, as well as data from retreatment trials with "induction" doses of PEG-IFN or high-dose RBV in prior non-responders to IFN-based therapy will be reviewed here. The possibility of shorter duration of therapy for genotype 2 and 3 patients based on recent publications and presentations will be discussed as well.

Thrombocytopenia (platelet count <150,000/microL) is a common complication in patients with chronic liver disease (CLD) that has been observed in up to 76% of patients. Moderate thrombocytopenia (platelet count, 50,000/microL-75,000/microL) occurs in approximately 13% of patients with cirrhosis. Multiple factors can contribute to the development of thrombocytopenia, including splenic platelet sequestration, bone marrow suppression by chronic hepatitis C infection, and antiviral treatment with interferon-based therapy. Reductions in the level or activity of the hematopoietic growth factor thrombopoietin (TPO) may also play a role. Thrombocytopenia can impact routine care of patients with CLD, potentially postponing or interfering with diagnostic and therapeutic procedures including liver biopsy, antiviral therapy, and medically indicated or elective surgery. Therapeutic options to safely and effectively raise platelet levels could have a significant effect on care of these patients. Several promising novel agents that stimulate TPO and increase platelet levels, such as the oral platelet growth factor eltrombopag, are currently in development for the prevention and/or treatment of thrombocytopenia. The ability to increase platelet levels could significantly reduce the need for platelet transfusions and facilitate the use of interferon-based antiviral therapy and other medically indicated treatments in patients with liver disease.

Although epidemiologic studies have documented that hepatitis C virus (HCV)/human immunodeficiency virus (HIV) co-infected patients have accelerated fibrogenesis, especially those with CD4+ cell counts <200 cells/mm(3), the pathogenic mechanisms are poorly understood. We investigated whether severe immunodeficiency in co-infection is associated with changes in intrahepatic inflammatory cytokine mRNA levels. We measured interferon (IFN)-gamma, tumour necrosis factor-alpha, transforming growth factor (TGF)-beta(1), interleukin (IL)-4, IL-10, IL-12p35 and IL-12p40 mRNA levels by real-time PCR performed on liver samples from HCV mono-infected (n = 19) and HCV/HIV co-infected (n = 24) patients. Co-infected patients had decreased intrahepatic mRNA levels of IFN-gamma (P = 0.09), IL-4 (P = 0.05) and IL-12p35 (P = 0.04) compared with mono-infected patients, while IL-10 was increased (P = 0.07). In co-infected patients, IFN-gamma mRNA levels increased linearly with increasing peripheral CD4+ cell counts by 1.23 times relative to the calibrator for every 100 CD4+ cells/mm(3) increase (P = 0.02). No other cytokines were significantly associated with CD4+ cell counts. In conclusion, HIV-induced lymphopenia may result in hepatic inflammatory cytokine suppression in HCV/HIV co-infection. Intrahepatic IFN-gamma levels are significantly reduced in patients with advanced immunodeficiency. Further studies are needed to assess whether decreased IFN-gamma secretion by HCV-specific CD4+ cells may account for accelerated fibrogenesis in these patients.