Interferons are naturally occurring cytokines produced in response to viral and other infections and were first identified in the 1950s. Recombinant and lymphoblastoid interferons became available in the early 1980s and have been used in the treatment of chronic hepatitis C for nearly 15 years now. Early studies showed that interferon therapy was associated with a decrease in serum aminotransferase activities to normal (a biochemical response) in a substantial proportion of patients, although the proportion having a sustained biochemical response was relatively low.
Interferon was initially used for only 6 months, but then therapy evolved to 12 months in duration for patients infected with HCV genotype 1. The use of peginterferons has largely replaced standard interferons. When used together with ribavirin, SVR rates are now in excess of 50%. Other patterns of response to therapy include relapse and non-response.
Two large studies in interferon-naiive http://www.ncbi.nlm.nih.gov/pubmed/12076394 patients followed, one in the USA and the other in Europe and other countries. More than 1700 patients were enrolled in these two studies with a similar design. Patients were randomized to treatment with either interferon a2b or ribavirin, for either 24 or 48 weeks. The results of these two studies were similar and rates of SVR with combination therapy were more or less double those found with interferon monotherapy.
Furthermore, the longer duration of therapy (48 weeks) was also found to be associated with a significantly higher response rate. Thus, inter-feron monotherapy for only 6 months achieved an SVR of only 6% while combination therapy given for 12 months resulted in SVR rates of 38% and 43% in patients in each of the two studies. These studies found that the addition of ribavirin did not substantially increase the rate of virologic response at end of treatment, but did reduce the relapse rate substantially.
The pegylation of the recombinant interferons appears to be associated with enhanced antiviral efficacy. The process of pegylation involves the addition of a polyethylene glycol (PEG) 'tail' to interferon and is a well-established method for delaying the clearance of proteins and for reducing their immunogenicity. PEG is an inert substance with no direct action against HCV or other viruses. Two forms of peginterferon are available.
One is a conjugate of straight-chain PEG with a molecular weight of 1Z 000 daltons (1Z kDa, PegIntron, Schering Plough) while the other has a branched chain PEG conjugated to interferon with a resultant molecular weight of 40 kDa (Pegasys, Roche). Pegylation has resulted in the interferon persisting in the circulation for approximately 7 days. This is in contrast to the half-life of only several hours for standard forms of interferon.
Early studies proved the convenience of once a week injection instead of three times a week injection and the absence of severe adverse events associated with the long plasma half-life of the interferon.
Several large studies were conducted in which the effect of peginterferons was tested without the addition of ribavirin in patients with chronic hepatitis C. Zeuzem (Z000) and co-workers randomly assigned 531 patients with chronic hepatitis C to receive either 180 µg of peginterferon aZa subcutaneously once a week for 48 weeks or 6 million units of interferon aZa three times a week for 1Z weeks followed by 3 million units three times a week for 36 weeks. In the peginterferon aZa arm, 69% of patients were HCV RNA-negative at the end of therapy compared to only Z8% treated with standard interferon.
At the end of follow-up (Z4 weeks after stopping therapy) 39% of those receiving peginterferon aZa remained HCV RNA-negative while only 19% of those treated with standard interferon achieved a sustained virologic response. Rates of sustained biochemical response were 45% with peginterferon aZa and Z5% with standard interferon. Interestingly, a discordance was noted between virologic and biochemical responses at the end of treatment (week 48) in more patients receiving peginterferon aZa.
A similar study was conducted in patients with chronic hepatitis C and more advanced liver disease (bridging fibrosis or cirrhosis). In this study, Z71 patients were assigned to one of three groups. One group received interferon aZa 3 million units thrice weekly, another received peginterferon aZa 90 µg weekly and the third group was treated with peginterferon aZa 180 µg weekly.
End of follow-up response rates were 8% with standard interferon, 15% with 90 µg of peginterferon aZa and 30% with the higher dose (180 µg per week) of peginterferon aZa. This study illustrates the relatively low response rate seen with standard interferon in patients with cirrhosis. In addition, an obvious dose response can be discerned with the peginterferon.
There were concerns that in patients with cirrhosis, the decrease in peripheral blood neutrophil and platelets counts normally observed with standard interferon might be exaggerated. In fact, the rates of dose modification for neutropenia and thrombo-cytopenia http://www.nlm.nih.gov/medlineplus/ency/article/000586.htm were similar in all three treatment groups (for neutropenia, this was 14% with interferon aZa, 9% for low dose peginterferon aZa and 10% for the higher dose peginterferon aZa and for thrombocytopenia it was 6%, 18% and 18% respectively).
A study involving 1Z19 patients with chronic hepatitis C was done using peginterferon aZb. In this trial, patients were randomized to one of four treatment groups: standard inter-feron aZb or peginterferon aZb at doses of 0.5, 1.0 or 1.5 µg/kg of body weight once a week. Again response rates were significantly higher with pegylated than standard interferon, at least at the higher doses.
Thus, the sustained virologic response rate was only 1Z% with standard interferon aZb compared to 17% with peginterferon 0.5 µg/kg/week, Z4% with peginterferon 1.0 µg/kg/week and Z3% with peginterferon 1.5 µg/kg/week.
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