Hepatology Focus: Update on Hepatitis C Treatment
Hepatology Focus: Update on Hepatitis C Treatment
Although screening of blood products and other interventions such as clean-needle exchange programs have significantly reduced the incidence of acute hepatitis C in the United States and elsewhere, there remains a large reservoir of chronically infected individuals, many of whom are unaware of their infection. Current estimates suggest a seroprevalence of 1.8% among Americans, most of whom are viremic. The clinical burden of chronic hepatitis C virus (HCV) infection is expected to increase over the next 2-3 decades as a large cohort of patients infected between the 1960s and 1980s, primarily as a result of recreational drug use, develops progressive liver disease. Between 8000 and 10,000 deaths each year in the United States are believed to be caused by infection with HCV -- which is now the most frequent indication for liver transplantation.
Even before identification of HCV, interferon-alfa (IFN-alfa) had been evaluated as a potential therapy for what had been called chronic non-A, non-B hepatitis.
Further studies using normalization of serum alanine aminotransferase (ALT) levels and improvement in liver histology as endpoints demonstrated the efficacy of IFN-alfa as therapy for the causative agent of chronic non-A, non-B hepatitis (HCV). Subsequent advances in molecular diagnosis have now increasingly allowed establishment of virologic criteria to evaluate efficacy of treatment in patients with chronic hepatitis C (see Table).
End-of-treatment response (ETR) refers to absence of viremia (ie, serum HCV RNA below level of detection) at completion of therapy. Sustained response (SR) indicates persistent absence of serum HCV RNA 6 months or more after cessation of therapy. A study by Marcellin and coworkers on the long-term clinical outcome in 80 patients with chronic HCV followed for a mean of 4 years following therapy highlighted the clinical implications of a virologic SR. Persistent absence of HCV RNA from serum was observed in 96% of patients with a lack of histologic progression on serial liver biopsy. In addition, ALT levels were persistently normal in over 90%. The most recent follow-up biopsy showed normal or near normal histologic findings in 62% of these patients. Thus, virologic SR was shown to be associated with both an absence of detectable serum HCV RNA and marked histologic improvement.
Relapsers are defined as patients who have undetectable serum HCV RNA at completion of therapy but who subsequently redevelop viremia. Nonresponders (NRs) are patients who fail to clear HCV RNA from serum during therapy.
A recent paper by Everson and associates underscores the importance of HCV RNA testing in defining treatment response. In patients with marked fibrosis and cirrhosis, they found a major discrepancy between biochemical (ALT) and virologic (HCV RNA) responses to therapy. Two of 7 (29%) patients with marked fibrosis and 2 of 6 (33%) patients with cirrhosis cleared HCV RNA without normalizing ALT. In contrast, only 3 patients (10%) without significant fibrosis had an HCV RNA response without normalization of ALT. Thus, clinical trials for chronic HCV are now typically reported using virologic response rates.
What then are the current goals of antiviral therapy in patients with chronic hepatitis C? Immediate goals are eradication of viral replication and improvement in hepatic inflammation and fibrosis. Long-term potential goals include prevention of cirrhosis, hepatocellular carcinoma, and liver failure.
Although screening of blood products and other interventions such as clean-needle exchange programs have significantly reduced the incidence of acute hepatitis C in the United States and elsewhere, there remains a large reservoir of chronically infected individuals, many of whom are unaware of their infection. Current estimates suggest a seroprevalence of 1.8% among Americans, most of whom are viremic. The clinical burden of chronic hepatitis C virus (HCV) infection is expected to increase over the next 2-3 decades as a large cohort of patients infected between the 1960s and 1980s, primarily as a result of recreational drug use, develops progressive liver disease. Between 8000 and 10,000 deaths each year in the United States are believed to be caused by infection with HCV -- which is now the most frequent indication for liver transplantation.
Even before identification of HCV, interferon-alfa (IFN-alfa) had been evaluated as a potential therapy for what had been called chronic non-A, non-B hepatitis.
Further studies using normalization of serum alanine aminotransferase (ALT) levels and improvement in liver histology as endpoints demonstrated the efficacy of IFN-alfa as therapy for the causative agent of chronic non-A, non-B hepatitis (HCV). Subsequent advances in molecular diagnosis have now increasingly allowed establishment of virologic criteria to evaluate efficacy of treatment in patients with chronic hepatitis C (see Table).
End-of-treatment response (ETR) refers to absence of viremia (ie, serum HCV RNA below level of detection) at completion of therapy. Sustained response (SR) indicates persistent absence of serum HCV RNA 6 months or more after cessation of therapy. A study by Marcellin and coworkers on the long-term clinical outcome in 80 patients with chronic HCV followed for a mean of 4 years following therapy highlighted the clinical implications of a virologic SR. Persistent absence of HCV RNA from serum was observed in 96% of patients with a lack of histologic progression on serial liver biopsy. In addition, ALT levels were persistently normal in over 90%. The most recent follow-up biopsy showed normal or near normal histologic findings in 62% of these patients. Thus, virologic SR was shown to be associated with both an absence of detectable serum HCV RNA and marked histologic improvement.
Relapsers are defined as patients who have undetectable serum HCV RNA at completion of therapy but who subsequently redevelop viremia. Nonresponders (NRs) are patients who fail to clear HCV RNA from serum during therapy.
A recent paper by Everson and associates underscores the importance of HCV RNA testing in defining treatment response. In patients with marked fibrosis and cirrhosis, they found a major discrepancy between biochemical (ALT) and virologic (HCV RNA) responses to therapy. Two of 7 (29%) patients with marked fibrosis and 2 of 6 (33%) patients with cirrhosis cleared HCV RNA without normalizing ALT. In contrast, only 3 patients (10%) without significant fibrosis had an HCV RNA response without normalization of ALT. Thus, clinical trials for chronic HCV are now typically reported using virologic response rates.
What then are the current goals of antiviral therapy in patients with chronic hepatitis C? Immediate goals are eradication of viral replication and improvement in hepatic inflammation and fibrosis. Long-term potential goals include prevention of cirrhosis, hepatocellular carcinoma, and liver failure.