Future Directions in Hepatitis C Therapy

KEY POINTS

• Special populations and therapy-resistant patients drive the search for new strategies and therapies for chronic HCV infection.
• Viramidine, a prodrug of ribavirin, shows promise as a potential alternative to ribavirin that is less likely to cause anemia, but further studies are needed.
• New classes of drugs that attack specific targets in HCV replication, such as protease inhibitors and polymerase inhibitors, show promise against HCV infection but bring problems of their own, such as increased risk of viral resistance.
• The future of hepatitis C therapy is likely to involve combinations of these new small-molecule drugs and PEG-IFN-based treatment.

Despite substantial advances in the treatment of chronic HCV infection, many unmet needs remain, prompting further evolution of therapeutic approaches. This evolution is unfolding on three fronts: through efforts to improve adherence (and thus response) in difficult-to-treat and understudied patient populations; through studies of new combinations of drugs in the current IFN-based regimen model; and through investigations of new drug classes.

A number of patient populations were not included in the initial registration trials of new anti-HCV therapies, leaving gaps in our understanding of how these patients may or may not respond to these therapies. Many of these populations are the same ones that are less likely to respond to current therapies, such as patients with HIV coinfection, African Americans, liver or renal transplant recipients, and active substance abusers. These understudied and inadequately managed populations also include those whose therapy has been compromised by dose-limiting side effects.

These patients drive much of the research into new therapies for HCV infection, but they also are now the subjects of numerous ongoing trials to determine whether current IFN-based therapy can be better used, perhaps in conjunction with adjunctive therapies to manage side effects, to meet these populations' special needs. While results from these studies are eagerly awaited, they are likely to show fairly modest improvements in response.

Another area of investigation has been the use of new combinations of antiviral drugs in IFN-based regimens, particularly the use of ribavirin-like drugs that may be associated with less dose-limiting anemia if used in place of ribavirin. Although several of these agents have been studied, only one, viramidine, has shown much clinical promise to date.

Viramidine is a prodrug of ribavirin that preferentially targets the liver. It has the potential for less accumulation in red blood cells and, therefore, less association with hemolytic anemia. An ongoing randomized trial in 180 treatment-naïve patients has found that combination therapy with PEG-IFN plus viramidine was associated with anemia in significantly fewer patients than was combination therapy with PEG-IFN plus ribavirin through 24 weeks of therapy (incidence of anemia, 2% vs 24%; p < 0.001).²²⁶ At 24 weeks, there was no difference between the groups in the proportion of patients with undetectable HCV RNA or a 2-log or greater decrease in viral load (83% in both groups).

If the final results from this phase II trial show at least comparable rates of sustained virologic response between the viramidine and ribavirin groups, and if these findings are confirmed in ongoing phase III trials, viramidine will emerge as a promising and less-toxic alternative to ribavirin for use in combination therapy.

New drug classes that represent novel therapeutic approaches to HCV infection (Figure 14) offer even more promise but also more uncertainty. The new class with the most short-term potential is the enzyme inhibitors, particularly protease inhibitors and polymerase inhibitors, which are designed to attack specific targets in HCV replication. Two other novel approaches, involving antisense oligonucleotides and ribozymes, have not proved very promising to date.

The rationale for using protease inhibitors in HCV infection is to attack the virus in a manner similar to the HIV model, where protease inhibitors have met with dramatic success. Several protease inhibitors are now in clinical testing in HCV-infected patients; of these, BILN 2061 is furthest in development and was recently shown to induce a 3-log to 4-log drop in HCV RNA levels over 48 hours of therapy in patients with HCV genotype 1.²²⁷ Its antiviral effect was much less pronounced in patients with genotypes 2 or 3. Further testing of BILN 2061 is on hold because of histologic evidence of cardiovascular toxicity in monkeys given the drug for 4 weeks.

Despite evidence of profound short-term viral suppression, a role for protease inhibitors could be complicated by factors even beyond potential safety concerns. First, the suppression of HCV by protease inhibitors appears to end upon treatment discontinuation, which could require prolonged courses of therapy, as in HIV infection. This would argue for restriction of protease inhibitors solely to confirmed nonresponders for whom viral suppression was critical. Second, the use of protease inhibitors raises the specter of HCV mutations and potential development of viral resistance not unlike that seen with HIV. This will clearly require caution and vigilance. Finally, it is probable that use of protease inhibitors in HCV infection will still require combination regimens, most likely including multiple enzyme inhibitors and perhaps other immunomodulators.

The HCV polymerase inhibitor that is furthest in clinical development is known as NM 283. It is active against HCV in chimpanzees, and in human phase I/II studies it has yielded a dose-related 0.5-log to 1-log reduction in HCV RNA after 2 weeks of therapy.²²⁸ While this antiviral effect is more modest than that of protease inhibitors, it suggests that polymerase inhibitors may be useful for improving response in combination with IFN-based therapy.