Mitchell Shiffman, MD, Associate Professor of Medicine, Chief, Hepatology Section, Medical College of Virginia, Richmond, Virginia
Mitchell Shiffman, MD
Mitchell Shiffman, MD is an Associate Professor and chief of the Hepatology Section at the Medical College of Virginia Commonwealth University. He is also the Medical Director for the Liver Transplant Program at the Medical College of Virginia Hospitals. Dr. Shiffman received his MD degree from the State University of New York, Upstate Medical Center in Syracuse. He completed his internship and residency training in Internal Medicine and fellowship training in Gastroenterology and Hepatology, at the Medical College of Virginia. Dr. Shiffman’s research is focused on developing new treatments for chronic viral hepatitis and understanding how the immune system interacts with HCV. He has participated in numerous clinical trials over the past decade, with the goal of developing more effective treatments for chronic viral hepatitis B and C.
Approximately 3.9 million (1.8%) Americans are infected with the hepatitis C virus (HCV). Chronic HCV infected can lead to cirrhosis, liver failure and hepatocellular carcinoma. HCV related chronic liver disease accounts for 8,000 to 10,000 deaths annually in the US. Moreover, theincidence of hepatocellular carcinoma in the US is rising, nearly doubling from the late 1970s to the early 1990s.
The basis for treatment of chronic HCV is immune modulation. This is accomplished by administering standard interferon alfa three times weekly with or without ribavirin. This thrice weekly dosing regimen of interferon was developed empirically by treating patients with chronic non-A, non-B hepatitis and monitoring serum levels of alanine aminotransferase (ALT). These studies were performed before HCV had been identified and a test for the virus developed. Given this limitation, it is not surprising that standard doses of interferon are largely ineffective at eradicating chronic HCV. Indeed, biochemical response rates (normalization of ALT levels) at the end of treatment with standard interferon generally range from 40 to 50%, with sustained response rates (6 months post-treatment) dropping to 15 to 20%. Virological response rates (undetectable serum HCV RNA by a reliable and sensitive reverse-transcriptase-polymerase chain reaction assay) range from 30 to 40% at treatment endpoint and from 10 to 20% at 6 months post-treatment.
Higher doses of interferon can be administered by increasing the dose or the frequency of administration. This approach appears to be associated with an increased rate of viral eradication during therapy and a higher end-of-treatment response. Unfortunately, the incidence of relapse remains high, and as a result, higher doses or induction dosing does not appear to substantially increase sustained response rates. Use of ribavarin along with interferon does increase the rate of sustained virologic response however, in individuals with genotype 1 sustained response following combination therapy is limited to 25 to 30%. Like interferon, ribavirin acts by modulating the immune response. Significant adverse effects associated with ribavirin can limit the use of combination therapy in some individuals.
There are also a number of patient, disease and virological factors that reduce the rate of response to treatment in patients with HCA infections, including cirrhosis, high pretreatment viral loads, type 1 genotype, liver histology, male sex, older age, viral co-infection and alcohol intake. These factors also predict progression to more severe disease, hepatic decompensation, hepatocellular carcinoma and death. The increased understanding of the natural history of HCV infection suggests that early aggressive intervention, maintenance of sustained antiviral pressure, and prolonged therapy would improve the efficacy of interferon therapy