Original articles report and assess current issues of concern in gastroenterology
PEGylated Interferons: Novel therapy for HCV
December 11, 2000
Hepatitis C is the most common cause of chronic liver disease in the U.S. today with a potential 4 million people exposed to HCV. Chronic viremia is seen in 80% of patients and clinical liver disease with a progressive hepatitis is present in up to 50% of individuals exposed to the virus. HCV is the most common cause of cirrhosis, liver failure, liver transplantation and hepatocellular carcinoma. The medical and economical impact of HCV over the next decade includes an 80% increase in HCV-related cirrhosis, a three-fold increase in HCV related deaths and an annual healthcare cost as high as $150 billion. In order to make an impact on these frightening statistics, we need to recognize and treat at least 30% of patients infected with HCV.
The good news is that over the last 10 years we have developed very effective therapies for HCV and that Rebetron (interferon plus ribavirin) therapy is associated with a 40% viral eradication rate. Viral eradication that is sustained 6 months after stopping therapy has been associated with a biochemical, virological and histological remission that is sustained for up to 10 years post treatment and is an effective cure for HCV. The challenge in therapy is to improve on this 40% sustained response rate and in particular to improve the response in the subgroup of patients who have genotype 1 virus and in whom response rates to Rebetron are only 25%. In an attempt to improve the response rate in this subgroup, higher doses of interferon with daily therapy and induction therapy have been used. These seemed to increase response rates but are associated with patient inconvenience and increased discomfort leading to poorer compliance. The development of PEGylated interferons now enables us to effectively deliver higher daily doses with better patient compliance and comfort. In this article we will discuss some of the efficacy data on these newer PEGylated interferons in HCV and evaluate their role in future therapy of HCV.
PEGylation of proteins is achieved by the addition of a polyethylene glycol (PEG) moiety onto the interferon molecule. PEG is a nontoxic polymer readily excreted into the urine and the size varies depending on the number of repeating units.
PEG can be linear or branched and can be conjugated to proteins via ester, amide, carbamate or urethane linkages.
The clinical value of PEGylation is to improve the pharmacokinetics of interferon thereby improving efficacy and the therapeutic index. Benefits include optimizing absorption and distribution, reducing clearance and decreasing immunogenicity.
There are currently two PEGylated interferons, PEG-Intron which is a 12Kda linear PEG attached to interferon alpha2 beta and Pegasys, a 40Kda branched PEG attached to interferon alpha2 alpha. Pharmacokinetic studies show that both these PEG-interferons can be administered once weekly by subcutaneous injection and that the area under the curve is maximal with PEG-Intron at 1.0 or 1.5 mcg/kg and for Pegasys at a fixed dose of 180mcg weekly. These doses were shown to be efficacious, safe and well-tolerated and are the doses studied in clinical phase 2 and 3 trials.
PEG-Intron: A large multicenter U.S. study for PEG-Intron has recently been completed where treatment naive patients were randomized to three doses of PEG-Intron once a week versus standard Intron A tiw (Popup Figure 1). The study population was typical for U.S. trials with 63% male, 91% Caucasian, 70% Genotype 1, 74% viral load greater than 2 million and 10% cirrhosis. PEG-Intron was twice as efficacious as Intron A in the 1.0 and 1.5 mcg/kg doses with sustained viral response rates as high as 25% for PEG-Intron versus 12% for Intron A (Popup Figure 2). Medication was well-tolerated with no new adverse events noted from the PEG-Intron compared to standard interferon. Injection site reactions were more common with PEG-Intron.