Original articles report and assess current issues of concern in gastroenterology

PEGylated Interferons: Novel therapy for HCV

Nezam H. Afdhal MD
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.

Clinical Trials
Several clinical trials have now been reported for the PEGylated interferons. We will review the major studies for both agents as monotherapies.

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.

PEGASYS: A large non-U.S. based study in 531 patients naive patients has been completed comparing Pegasys 180mcg weekly to a regimen of Roferon-A of 6mU tiw for 12 weeks followed by 3mU tiw for 36 weeks, All patients received 48 weeks of treatment and 24 weeks follow up. The study population was 67% male, 85% Caucasian, 13% cirrhosis, 63% genotype 1 and a median viral load of 7.4 million. The sustained response rate was 19% for Roferon-A and 39% for Pegasys, once again double the response compared to tiw dosing.

Another study of Pegasys at 90mcg and 180mcg weekly versus Roferon-A 3mU tiw was performed in 271 patients with cirrhosis or advanced fibrosis. The sustained virological response overall was 30% but this was predominantly confined to Genotype 2 and 3 patients who received the 180mcg dose of Pegasys (Popup Figure 3).

PEGylated interferons hold much promise and will probably become the preferred interferons for therapy of HCV. We expect to see both improved patient compliance with weekly injections and double the efficacy of standard interferon monotherapy. However, the side-effect profile is similar, and issues of management of these patients will not change. In addition, neither form of PEGylated interferon is as effective as combination Rebetron in eradicating HCV. Therefore, Rebetron, with a 41% sustained response rate, will probably remain the first choice of therapy in the majority of patients. Initially a role for PEGylated interferons may be confined to patients with cardiac disease, prior history of hemolysis, renal disease with impaired creatinine clearance or those on dialysis and patients on maintenance therapy to prevent fibrosis or hepatocellular cancer. The next anticipated true advance will be the addition of ribavirin to PEGylated interferons. Initial preliminary studies and predictions from larger ongoing studies suggest that this combination of PEGylated interferon plus ribavirin may increase the sustained response rate to above 50% (Popup Figure 4). The future certainly looks promising for the therapy of HCV.


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