Only about half of all people treated for hepatitis C with pegylated interferon and ribavirin achieve a sustained virologic response (SVR), defined as an undetectable hepatitis C viral load six months after the end of treatment. Among those who don't achieve an SVR, three patterns have been described:
- Relapsers: people whose viral load becomes undetectable during therapy, but later returns to detectable levels
- Partial responders: people who experience a significant drop in viral load during therapy, but never become undetectable
- Non-responders: people who never experience a meaningful drop in viral load during therapy
These three categories are often lumped together as "non-responders" despite differences between the groups. For example, people who respond at all to treatment -- relapsers and partial responders -- may experience some benefit from therapy, even without an SVR, in the form of an improvement in the condition of their liver (called a histologic response, generally marked by a reduction in liver inflammation). In theory, relapsers might benefit from a longer course of treatment, but extending treatment probably would not help non-responders.
Some people who did not achieve an SVR using earlier, less effective forms of treatment (standard interferon alone or with ribavirin, or pegylated interferon alone) may achieve an SVR using pegylated interferon in combination with ribavirin. One recent report described 604 "non-responders" to standard interferon (with or without ribavirin) who were retreated with pegylated interferon (Roche's Pegasys) and ribavirin (abstract here). Only 18% achieved an SVR. An SVR was more likely in people who had never taken ribavirin before, people who were able to stay on the full dose of ribavirin, and people who had hepatitis C genotype 2 or 3, which generally respond better to treatment. People with cirrhosis -- those in greatest need of successful treatment -- were less likely to achieve an SVR.
Another form of interferon, Infergen or consensus interferon, has been on the market for several years. Infergen is a synthetic form of interferon alpha, developed by Amgen and licensed to InterMune. Infergen is based on a consensus sequence of all interferon alpha subtypes -- hence the name "consensus interferon." Interferon alpha is a protein naturally produced in the body; our genes encode at least a dozen functional subtypes of interferon alpha -- variants of the protein with minor genetic differences. In contrast to Infergen, interferon alfa-2a (Roferon-A; Roche) and interferon alfa-2b (Intron A; Schering-Plough) are recombinant forms of interferon alpha based on a single subtype.
By some measures, Infergen demonstrates higher levels of antiviral activity than interferon alfa-2a and interferon alfa-2b in test tube studies. Studies of Infergen used as monotherapy for chronic HCV showed efficacy and tolerability comparable to or better than interferon alfa-2b . A preliminary analysis of a thrice-weekly regimen of Infergen in combination with daily ribavirin showed a sustained virologic response of 55%, compared with 31% among patients treated with standard interferon alfa-2b and ribavirin. In small, open-label studies, treatment with Infergen and ribavirin produced sustained virologic responses in some individuals who did not respond to or relapsed after prior interferon alfa treatment, suggesting a role as second-line therapy.
Infergen's use in clinical practice is minimal compared to Roche and Schering’s pegylated interferons. Use of Infergen was initially limited due to the superiority of combination therapy with interferon alpha and ribavirin. When originally approved, ribavirin was only available for use with Schering’s interferon alfa-2b (Intron A). Schering bundled ribavirin with Intron A, so that ribavirin was not sold separately to be combined with other interferons. While Schering now markets ribavirin separately, standard interferon has been supplanted by more effective pegylated forms that only need to be taken once a week. Infergen doesn't come in pegylated form, though InterMune initiated a pilot study of a pegylated version of Infergen in early 2003.
Yesterday, InterMune announced a new focus on researching and promoting the use of Infergen in non-responders. They'll start a large study of combination therapy with Infergen and ribavirin in the coming months. InterMune is also doing a smaller study of Infergen in combination with Actimmune, another InterMune drug that's a synthetic version of interferon gamma (an interferon protein with overlapping but distinctive antiviral effects). Finally, InterMune is working on developing protease inhibitors for hepatitis C, though none are in human studies yet.
If Infergen has an advantage, it's that some partial responders and non-responders to current treatment may get better results with Infergen. InterMune estimates that there are 150,000 non-responders to treatment in the United States, and that number is growing by 50,000 each year. Drawbacks with Infergen include the side effects common to all interferon treatment, and the fact that unless InterMune pursues further development of a pegylated form, Infergen requires injections three times a week.
InterMune would do well to target their research efforts to people most in need of effective treatment -- those with cirrhosis, people with genotype 1 (considered the hardest to treat), African-Americans and people with HIV (two groups with lower chances of achieving an SVR).
Related: see the follow-up post from May 10, 2004: Intermune and Infergen Interlude