William F. Balistreri, MD
What are our evidence-based treatment strategies for hepatitis C? Will we ever have an interferon-free regimen?
Response from William F. Balistreri, MD
Professor of Medicine, University of Cincinnati College of Medicine; Staff Physician, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
The Current Standard Treatment for HCV Infection
Combination therapy with pegylated interferon and ribavirin has long been the standard of care for patients with chronic hepatitis C (HCV) infection. Although effective in achieving high response rates, this regimen is associated with troublesome side effects. Therefore, the development and approval of effective protease inhibitors, telaprevir and boceprevir, was hailed as a new era of therapy for patients with hepatitis C genotype 1 infection.[2,3]
Interferon-Free Treatment: No Longer a Dream?
Several studies were presented at both Digestive Disease Week (DDW) 2012 in May and at the European Association for the Study of the Liver (EASL) annual meeting in April 2012 that documented that these direct-acting antiviral agents allow more effective and shorter durations of treatment. For example, in patients infected with HCV genotype 1 for whom previous standard therapy failed to eliminate the virus, treatment with either of these protease inhibitors was shown to be significantly more effective, with sustained viral response rates 2- to 3-fold higher than with traditional therapy.
An American Association for the Study of Liver Diseases plenary session presentation during DDW 2012 reported that when telaprevir was used in combination with pegylated interferon and ribavirin, the dose of ribavirin could be substantially reduced. Reduction of the ribavirin dose to less than 600 mg/day had no substantial effect on sustained viral response (SVR) rates in patients who received telaprevir combination treatment. In another study, when boceprevir was used in combination with pegylated interferon and ribavirin, SVR was achieved in patients who had been nonresponsive to previous therapy.
Despite the optimism about the prospects for this treatment of HCV, the fact that telaprevir and boceprevir must be used in combination with pegylated interferon and ribavirin is a persisting concern. This is far from the ideal regimen. In fact, because of poor tolerability, many treatment candidates will decide not to pursue treatment or to defer treatment until a simpler regimen is available. However, other studies suggest that an interferon-free regimen (and perhaps even a ribavirin-free regimen) is no longer a dream. Various compounds encompassing several distinct drug classes are currently under development. These drugs bring us one step closer to the long sought-after ideal: the ability to remove interferon injections from treatment for HCV.
Targeting Novel Treatment Options
Two studies presented at the EASL annual meeting in April 2012 revealed novel treatment options for HCV genotype 1-infected patients who are unable to take interferon-based therapy. The strategy was based on a 12-week combinations of DAA (direct-acting antiviral) interferon-free therapy.
In the first study, ABT-450, a potent inhibitor of the HCV NS3 protease, was coadministered with ritonavir (ABT-450/r), a CYP3A inhibitor, to maintain high ABT-450 exposures and support once-daily dosing. ABT-072 is a non-nucleoside inhibitor of HCV NS5B polymerase. The investigators reported that 91% of treatment-naive, noncirrhotic patients infected with HCV genotype 1 (the interleukin-28B CC genotype) achieved SVR after 12 weeks, and 82% achieved SVR at 36 weeks. The combination of ABT-450/r plus ABT-072 plus ribavirin was well tolerated over the 12 weeks of treatment.
In a companion study, ABT-450/r was coadministered with ABT-333, another non-nucleoside inhibitor of HCV NS5B polymerase. The combination of ABT-450/r plus ABT-333 plus ribavirin without interferon in HCV genotype 1-infected patients was well tolerated during 12 weeks of treatment. Overall, 93%-95% of treatment-naive patients infected with HCV genotype 1 achieved SVR after 12 weeks of treatment. Therefore, ABT-450/r plus ABT-333 plus ribavirin for 12 weeks has the potential to achieve SVR in a high proportion of patients without the use of interferon. Further trials of these agents are under way.
Predicting Response and Nonresponse
In the interim, how can we tailor therapy and predict response rates? Investigators reported that patients infected with HCV genotypes 2 and 3 achieved SVR rates of 70%-80% in clinical trials. However, in real-life settings, lower SVR rates in the range of 55%-65% are reported. In work presented at DDW 2012, predictive factors for nonresponsive patients with genotypes 2 and 3 included daily alcohol intake greater than 40 g, HIV coinfection, low thyroid-stimulating hormone levels, the presence of cirrhosis, and the duration of infection. These risk factors should be assessed and may suggest the need for an intensified treatment course.
Further data presented at DDW 2012 documented the value of a major genetic predictive factor: a single nucleotide polymorphism in the upstream region of the interleukin-28B gene. Genotype CC was the strongest factor predictive of SVR in patients with HCV genotype 1 who were treated with pegylated interferon and ribavirin. This CC genotype was also shown to be associated with a significantly higher rate of spontaneous clearance in both white and black patients with exposure to HCV. This information will be of value when counseling patients.
The Bottom Line
The bottom line is that the intense interest in developing and validating new strategies for the treatment of chronic HCV promises to eliminate the need for interferon and perhaps even ribavirin.