At the 2010 Digestive Disease Week (DDW), several presentations highlighted new approaches to the treatment of hepatitis C virus (HCV) infection. The burden of HCV is rapidly increasing as those infected with the virus years ago are becoming symptomatic. New treatments may soon offer hope where standard treatments have been failing, but the cost is expected to soar. David R. Nelson, MD, Professor of Medicine, University of Florida, Gainesville, suggested that within a few years we could "cure 60% to 80% of HCV patients with these new treatments."
Treatment for HCV is only offered to about 20% of patients, and most patients are not diagnosed. The standard of care, with pegylated interferon (PEG-IFN) and ribavirin (PEG RBV), is not effective in the most common HCV—genotype 1: up to 50% of these patients do not respond to treatment.
Genetic studies may help select appropriate patients for standard therapies, thereby avoiding the cost and toxicity of treating patients who would not respond. Recent studies have identified a polymorphism on chromosome 19 that is strongly associated with a sustained viral response (SVR) to the regimen. In the landmark IDEAL (Individualized Dosing Efficacy versus Flat Dosing to Assess Optimal Peg Interferon Therapy) study of 1137 patients, those with the IL28B genotype had 5 times better odds of treatment success. Genetic testing will likely become a key component of HCV management.
Current regimens are also being optimized by other strategies, including response-guided therapy and maximum dosing of ribavirin. With response-guided therapy, patients who demonstrate a rapid viral response are treated for 24 weeks, then treatment is stopped. In the absence of a rapid response, patients are treated for 48 weeks, and those who completely respond then discontinue treatment. Patients who are partial responders are treated for 72 weeks. Nonresponders virtually never attain an SVR and need other approaches. For slow responders, studies are inconsistent as to whether continued treatment will be beneficial.
Protease Inhibitors for HCV
First-generation protease inhibitors (PIs) are expected to offer higher SVR rates for treatment-naïve (7%- 80%) and treatment-experienced (40%-50%) populations when added to standard PEG RBV. But these dramatic gains will be partially offset by challenges with viral resistance and new adverse effects.
The PI telaprevir, given along with PEG-IFN and RBV, produced high response rates among patients with previous relapse, viral breakthrough, or partial response to standard treatment, according to final results from a "rollover" study of telaprevir.
Andrew J. Muir, MD, of Duke University, Durham, NC, described this open-label study, in which 117 patients who failed to respond to PEG RBV (or relapsed) in phase 2 telaprevir trials were allowed to cross over to the telaprevir arm. Some 37% of patients who were null responders achieved an SVR, as well as 97% of patients who relapsed after standard therapy. In the control arm (patients who never received telaprevir after standard treatment), SVR rates remained low.
"These are very encouraging results," said Dr Muir. "We are awaiting phase 3 results, and if they are confirmed, we hope to have this drug available in the near future."
Telaprevir appears to have the ability to help overcome negative host and viral factors, but drug resistance will eventually emerge. To prevent this, the new drugs will need to be given with PEG RBV. "Ribavirin is critical for protease inhibitor combination therapy. SVR rates are reduced by 25% or more when RBV is not part of treatment regimen," Dr Muir noted.
Boceprevir is another promising PI and is associated with an SVR rate of 100% at 48 weeks when given after 4 weeks of standard therapy.
Promising New Approaches
Other promising agents are nucleoside and nonnucleoside RNA-polymerase inhibitors. Early indications are that the nucleoside polymerase inhibitors may have significant activity, regardless of HCV genotype, and may be associated with less resistance than other agents. Although these drugs may be more effective for HCV, they may still require PEG-IFN and RBV, and resistance may become the "new barrier."
Starting in 2011, the focus of treatment will be triple therapy—pairing a new PI with PEG RBV—with treatment duration guided by response. By 2014, quadruple therapy that adds a nucleoside or non-nucleoside inhibitor may be the standard. The addition of these agents will likely produce more adverse effects, and costs will likely be significant. Interferon-free regimens, and regimens that combine a PI and a polymerase inhibitor without PEG or RBV, are showing good efficacy and safety. As early as 2015, an interferon-free regimen could be available.