Hepatitis C is a major cause of liver disease leading to cirrhosis. Although interferon (IFN) is the only approved therapy, treatment is characterized by low response rates and dose-limiting side effects. We evaluated the addition of thymosin ␣1 (TA1), an immunomodulatory peptide, to the standard treatment regimen for hepatitis C to determine if combination therapy shows biological activity using outcome measures including normalization of alanine aminotransferase levels, histological activity, and viral load during treatment. We performed a randomized, double-blind, placebo-controlled trial to compare the biological activity of a combination TA1 and IFN with that seen for IFN alone in patients with chronic hepatitis C infection. One hundred nine patients were randomized for intention to treat and received 1.6 mg of TA1 subcutaneously twice weekly and 3 MU of IFN three times weekly; 3 MU of IFN three times weekly and placebo TA1; or placebo for both agents. All patients had chronic HCV infection with confirmation of chronic hepatitis on liver biopsy. Biochemical responders were followed up until alanine aminotransferase (ALT) levels became abnormal or for 26 weeks, and relapsers were retreated for 26 weeks in the same treatment arm. One hundred three patients completed treatment for 26 weeks, and six patients dropped out. The groups were similar with regard to sex, gender distribution, baseline histological activity index (HAI) score, risk factors, and viral titers.
End
-of-treatment biochemical response was seen in 37.1% of patients treated with combination therapy, 16.2% of patients treated with IFN alone, and 2.7% of untreated controls by intent-to-treat analysis (IFN/TA1 vs. IFN, 2 ؍ 4.05, P ؍ .04). HCV RNA clearance was seen in 37.1% of IFN/TA1-treated patients and 18.9% of IFN-treated subjects. Mean HCV RNA titers were significantly lower than baseline at weeks 8, 16, and 24 after drug initiation among patients treated with IFN/TA1 but not in the other treatment arms. Histological improvement, as evidenced by a decrease in HAI of more than two points, occurred in the combination therapy arm more frequently than in comparison groups. Cumulative sustained biochemical responses were 14.2% and 8.1% in the IFN/TA1 and IFN arms, respectively, based on an intention-to-treat model. The combination of TA1 and standard IFN treatment for chronic hepatitis C showed evidence of biological activity at the completion of treatment by biochemical, histological, and virological outcome measures. Further research involving longer duration and varied dosing is needed. (HEPATOLOGY 1998;27:1128-1135.)
Hepatitis C virus (HCV) infection has become recognized as a major pathogen worldwide and a frequent etiological factor in the development and progression of chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC). 1 In the United States, the Centers for Disease Control estimates that between 3.5 and 4 million individuals are infected with HCV. 2 Recently, hepatitis C emerged as the leading indication for liver transplantation. 3 Evidence is growing that treatment intervention may improve the outcome for this disease, including progression to cirrhosis and development of HCC. 4,5 Optimal treatment for chronic HCV infection remains an elusive goal. Although interferon (IFN) ␣2b clearly has some beneficial effect on a variety of treatment outcomes, including normalization of serum transaminase levels, histological scoring of inflammation and injury, and reduction of viral load, both end-of-treatment response (ETR) and sustained response (SR) rates leave room for improvement. 6,7 To this end, investigators have focused efforts on varying the dose and duration; use of other types of interferon, iron-reduction therapy, and other antiviral agents; and use of interferon in combination with other therapeutic agents. In this study, we describe the combination of IFN with thymosin ␣1 (TA1).
TA1 is an immunomodulatory peptide produced by the thymus gland and other cells. The 28-amino acid peptide is one member of the family of thymosins that collectively