Peginterferon alfa-2a in Chronic HCV & Cirrhosis or Bridging Fibrosis

Peginterferon alfa-2a in Chronic HCV & Cirrhosis or Bridging Fibrosis
New England Journal of Medicine, December 2000

Pegasys (Pegylated Interferon alfa-2a) in Patients with Chronic HCV

I just returned from the ACTG meeting in Wash DC where we discussed coinfection and the need to increase the focus on research addressing key unanswered questions. These are some key questions affecting coinfected persons: how do HIV meds affect HCV, does HIV impair response to HCV and HCV therapy, will coinfected persons respond as well to HCV therapy, when is the best time to start HCV therapy, how much does CD4 count & CD4 nadir affect response to HCV therapy, how does the virology of coinfection affect either disease, does ribivarin interaction reduce AZT/d4T effectiveness, can persons be treated effectively with HAART & HCV therapy simultaneously, how difficult will adherence be & can we build a support system for coinfected people taking HCV therapy. Another key question is who will treat HCV in coinfected patients: are ID docs prepared to meet this challenge, or will hepatologists have to work closely, perhaps together in clinic settings, with HIV treaters. The ACTG has agreed to increase their focus on coinfection research. As you know its estimated that 30% of HIV-infected individuals have HCV, and for persons infected with HIV thru IVDU the HCV infection rate is estimated to be 60-90%.

In the December New England Journall of Medicine, there are two reports on studies in HCV with Pegasys, the Roche version of pegylated interferon. These reports contain the fully published data sets of information that was first reported at previous conferences.

The first PDF is the report of a study first reported at last Spring's EASL Conference (European Ass for the Study of Liver Diseases) in Amsterdam. The data was reported on the NATAP web site and those reports can be found in the Conference Reports section on the web site. In this study 39% receiving Pegasys achieved a sustained virologic response compared to 19% for those receiving interferon alone (6 MU induction regimen pared down to 3 MU 3 times per week).

The second PDF is the published study on Pegasys in patients with cirrhosis or bridging fibrosis which found a 30% sustained virologic response to Pegasys. Bear in mind the standard of care for HCV is interferon + ribivarin. It is expected that response rates will improve when pegylated interferon is used with ribivarin. So far, we have not seen large scale study results from Pegasys+ribivarin, but at recent AASLD conference Peg Intron+ribivarin results were reported and show that ribivarin can be combined with pegylated IFN and does produce improved results compared to pegylated IFN alone. Ongoing studies are looking at Pegasys+ribivarin.

Abstract
Background. Covalent attachment of a 40-kd branched-chain polyethylene glycol moiety to interferon alfa-2a results in a compound (peginterferon alfa-2a) that has sustained absorption, a slower rate of clearance, and a longer half-life than unmodified interferon alfa-2a. We compared the clinical effects of a regimen of peginterferon alfa-2a with those of a regimen of interferon alfa-2a in the initial treatment of patients with chronic hepatitis C.

Methods
We randomly assigned 531 patients with chronic hepatitis C to receive either 180 µg of peginterferon alfa-2a subcutaneously once per week for 48 weeks (267 patients) or 6 million units of interferon alfa-2a subcutaneously three times per week for 12 weeks, followed by 3 million units three times per week for 36 weeks (264 patients). All the patients were assessed at week 72 for a sustained virologic response, defined as an undetectable level of hepatitis C virus RNA (<100 copies per milliliter).

Results
In the peginterferon group, 223 of the 267 patients completed treatment and 206 completed follow-up. In the interferon group, 161 of the 264 patients completed treatment and 154 completed follow-up. In an intention-to-treat analysis in which patients who missed the examination at the end of treatment or follow-up were considered not to have had a response at that point, peginterferon alfa-2a was associated with a higher rate of virologic response than was interferon alfa-2a at week 48 (69 percent vs. 28 percent, P=0.001) and at week 72 (39 percent vs. 19 percent, P=0.001). Sustained normalization of serum alanine aminotransferase concentrations at week 72 was also more common in the peginterferon group than in the interferon group (45 percent vs. 25 percent, P=0.001). The two groups were similar with respect to the frequency and severity of adverse events, which were typical of those associated with interferon alfa.

Conclusions
In patients with chronic hepatitis C, a regimen of peginterferon alfa-2a given once weekly is more effective than a regimen of interferon alfa-2a given three times weekly. (N Engl J Med 2000;343:1666-72.)

A few interesting points raised by study investigators:

Interferon is an essential component of the treatment of chronic hepatitis C virus (HCV) infection. However, treatment with interferon alone is generally associated with a sustained virologic response in fewer than 20 percent of patients. (1,2,3) A 48-week combination regimen of interferon alfa and ribavirin is associated with a sustained virologic response in 38 to 43 percent of patients. (4,5)

One of the reasons for the marginal response to interferon is its short half-life (approximately eight hours (6)), which leads to wide fluctuations in the plasma concentrations of the drug during the treatment period. Studies of viral kinetics indicate that HCV has a high rate of turnover and an in vivo half-life of only a few hours. (7,8) Among patients treated with interferon alfa three times weekly, an
intermittent increase in viral load can be observed on treatment-free days. (9) Covalent attachment of a 40-kd branched-chain polyethylene glycol moiety to interferon alfa-2a produces peginterferon alfa-2a, a compound that has sustained absorption, a slower rate of clearance, and a longer half-life than
unmodified interferon alfa. (10,11) The sustained high concentrations of peginterferon alfa-2a in plasma (12) maintain an antiviral effect on HCV and make possible once-weekly administration. We compared the efficacy and safety of peginterferon alfa-2a administered once per week with the efficacy and safety of interferon alfa-2a administered three times per week for 48 weeks.

A discordance between the virologic and the biochemical responses at week 48 was observed in more of the patients assigned to receive peginterferon alfa-2a than of those assigned to receive unmodified interferon. Patients who had a virologic response at week 48 but who did not have a normal serum alanine aminotransferase concentration at this time had a better histologic response at week 72 than did the entire study cohort or the subgroup of patients who had both a virologic and a biochemical response at week 48.

This finding indicates that peginterferon alfa-2a was not associated with long-term adverse effects on the liver. In addition, patients who had a virologic response but not a biochemical response at week 48 had better overall rates of virologic and biochemical responses at week 72 than patients who had both a virologic and a biochemical response at week 48. The reason for the better response in this subgroup of patients is not known, but it may be associated with a more pronounced immune response in the host and with the elimination of reservoirs of infected cells in these patients.