Interferon alpha-2A and interferon alpha-2B are very similar, both in terms of their molecular structure, their dosing and the response rates in their clinical trial. Consensus interferon has a slightly different molecular structure, which was made by combining several different interferon molecules in a computer and coming up with a consensus sequence. It's dosed differently, by micrograms rather than units, and may have a slightly different response rate, though certainly not reported in the literature to be as high as the pegylated interferon products.

Rajender Reddy MD: Pegylation of interferon is a process where there's an attachment of a polyethylene glycol molecule to interferon. The process of pegylation is not unique to interferon and is also not new. It has been around for quite some time, and there are quite a few pegylated products that are FDA-approved.

Attachment of a nontoxic polyethylene glycol molecule to a native protein alters the properties of the native protein, it prolongs the half-life of the native protein.

David Bernstein MD: That means that the patients are able to give themselves a single injection per week as opposed to three times a week. By doing that, one, it's easier for patients, it may improve compliance, and it certainly improves their quality of life, having to give one injection a week as opposed to three.

Othe important effects of the pegylation of interferon is that you have more medication present during the course of the week. That theoretically should eliminate the resistance seen to standard interferons, and, in fact, that has been proven with greater efficacy with interferon monotherapy using the pegylated products over the standard products.

Robert Brown MD: The mechanism of action of ribavirin is not fully known. As a monotherapy, it has no antiviral properties, but seems to lower the liver enzymes in the serum. We think that it serves predominantly as an immunomodulatory agent, but it's complete mechanism of action is not understood.

Rajender Reddy MD: When you look at on-treatment response with interferon alone versus interferon and ribavirin, there are only relatively small differences in terms of the on-treatment response, but when you look at relapse rates, when patients are treated with interferon alone, the relapse rate is much higher compared to those who receive interferon and ribavirin. So it appears that the major benefit of ribavirin is to decrease the relapse.

Robert Brown MD: The FDA-approved regimens that are the current standard of care for treatment of patients with hepatitis C are the two pegylated interferons, pegylated interferon alpha-2A, which is dosed at 180 micrograms flat dose, once weekly and pegylated interferon alpha-2B which is dosed based on weight - 1.5 micrograms per kilo weekly, both of them in combination with ribavirin. The FDA approved doses of ribavirin vary for the two products. Pegylated interferon alpha-2A was tested with 1,000-1,200 milligrams per day of ribavirin whereas the alpha-2B product was tested with a flat dose of 800 [mg]. These are the FDA-approved regimens for all genotypes.

I'm frequently asked by my patients to compare the two pegylated interferons in combination with ribavirin. It is very hard without a head-to-head study to make any clear comparisons. The two drugs were tested in different patient populations, both in the United States and in Europe, and using different ribavirin dosing, 800 versus 1,000-1,200 [mg].

There are differences, however, in the labeling of the two drugs, particularly for genotypes 2/3. For genotypes 2/3, the label does allow for six months of therapy with the pegylated interferon alpha-2A and not for the alpha-2B. Similarly, the labeling for the alpha-interferon-2B product includes 800 mg of ribavirin.

That isn't to say that some investigators aren't using pegylated interferon alpha-2B for shorter courses in genotypes 2 /3 or using higher doses of ribavirin, 1,000-1,200 mg per day in patients who are genotype 1. They just have to be aware that that is an off-label utilization of the drug and inform their patients accordingly.

What are the differences in efficacy between PEG-IFN-based regimens and standard interferon-based regimens?

Robert Brown MD: Pegylated interferon and ribavirin has shown clinical superiority to standard interferon and ribavirin in patients who are naïve to therapy. The response rates to pegylated interferon and ribavirin, compared to standard interferon, are about 10% better. There are no studies of pegylated interferon and ribavirin that are published in non-responders. Standard interferon and ribavirin is FDA-approved for the treatment of interferon monotherapy relapsers.

Data on other subgroups is not yet available, and it's hard to make firm recommendations. It is likely that pegylated interferon and ribavirin will be superior to standard interferon and ribavirin in the treatment of interferon failures. What the efficacy will be in interferon and ribavirin combination therapy failures is not yet determined.

What alternatives are there for patients intolerant of standard treatment?

Robert Brown MD: Patients who cannot take ribavirin are divided into two groups. The first are patients who have contraindications to ribavirin. These would include patients on hemodialysis or those with some form of anemia that can't be treated.

The second group are patients who start on combination therapy with pegylated interferon and ribavirin but can't tolerate ribavirin due to anemia.

In the first group, the only option is pegylated interferon monotherapy. And though it has a lower response rate than combination therapy, response rates of up to 30% have been reported. In the second group, you may be able to maintain these patients on erythropoietin and lower doses of ribavirin. That certainly would be preferable to pegylated interferon monotherapy, in my opinion.

For patients who are intolerant to a prior course of interferon, I spend a lot of time trying to figure out what their intolerance is. If these were side-effects that could have been managed with improvement in side effect management, I think that those are potential patients for re-treatment with pegylated interferon and ribavirin. Patients who had severe side-effects of interferon, suicidal ideation, severe depression or unusual immunologic side-effects, those patients have contraindications to interferon-based therapy and should not be re-treated with pegylated interferon.

What are the contraindications to treatment of hepatitis C?

Robert Brown MD: Patients who have advanced psychiatric disease, particularly prior suicide attempts, should not be treated with interferon-based therapy. Also, patients who have severe coexisting comorbidities should not be treated. That would include unstable cardiac disease, uncontrolled diabetes or other life-threatening illnesses that make it unlikely that antiviral therapy will impact on their life expectancy.'

Rajender Reddy MD: Organ transplantation, particularly kidney transplantation, can be also considered an absolute contraindication for interferon therapy. Patients who have had liver transplantation, although this therapy is not an approved form, can be considered in select situations for interferon therapy.

Robert Brown MD: Ribavirin's defining toxicity is hematologic. It causes a hemolytic anemia. So patients who have severe anemia or unstable cardiac disease that couldn't tolerate some degree of hemolysis and anemia should not receive ribavirin. Ribavirin has also been shown to be teratogenic in animals and shouldn't be given to anyone who is pregnant or planning on getting pregnant during the course of therapy or six months after therapy has stopped.

Rajender Reddy MD: At least two forms of contraception prevention measures should be adopted by patients who undergo therapy with interferon and ribavirin. This is because of the fear of teratogenicity being induced by ribavirin.