Chronic infection with the hepatitis C virus (HCV), which affects 1-2% of adults in the United States, is a major risk factor for liver failure due to cirrhosis and/or hepatocellular carcinoma (Davis 2010). Epidemiological information suggests that the frequency of these HCV-related sequelae is likely to continue to increase over the next 10-15 years unless effective and well-tolerated treatments become available. Development of improved antiviral therapy is thus an important public health priority.
Until recently, the most effective treatment for chronic HCV infection has been a combination of peginterferon and ribavirin, given for up to 48 weeks. With this regimen, the sustained virological response (SVR), defined as undetectable HCV RNA 24 weeks after completion of antiviral treatment, is approximately 50-60% (Hoofnagle 2006). Not all patients are able to complete therapy however; up to 10% will discontinue this prematurely as a result of intolerable side effects, predominantly depression and/or fatigue (Seeff 2010). The major determinants of responsiveness to antiviral therapy are viral genotype and selected host characteristics. Hepatitis C genotype 1 (HCV-1), which accounts for approximately 70% of chronic infections in North America, and is relatively resistant to treatment with peginterferon and ribavirin. SVR with treatment for HCV-1 is approximately 40% (Hoofnagle 2006). That said, among HCV-1-infected individuals, there is diversity in SVR, which is correlated with a dinucleotide polymorphism at a locus upstream of the interleukin 28B (IL28B) gene. Specifically, with 48 weeks of peginterferon and ribavirin therapy, 70% of individuals with the IL28B CC polymorphism achieve SVR, compared with only 30% of individuals with other IL28B polymorphisms (Thompson 2010).
New treatments for chronic HCV-1 infection are now available. In May 2011, the Food and Drug Administration (FDA) approved telaprevir, an orally available small molecule inhibitor of the HCV-1 protease, for treatment of chronic HCV-1, to be given in combination with peginterferon and ribavirin. In HCV-1-infected patients, this three-drug regimen has been shown to confer an SVR of 75% (Jacobson 2011). However, this regimen appears to be associated with up to a nearly 1.5-fold increase in premature drug discontinuation, in comparison with a regimen of peginterferon, and ribavirin alone, largely influenced by the development of telaprevir-associated rash. Given the high responsiveness to conventional peginterferon and ribavirin among HCV-1-infected individuals with the IL28B CC polymorphism, we hypothesize SVR will not be enhanced in such individuals by the addition of telaprevir to peginterferon and ribavirin therapy. If this is correct, HCV-1-infected patients with the IL28B CC polymorphism can then be treated with comparable success with peginterferon and ribavirin alone and will therefore be spared telaprevir-associated adverse affects.
The proposed study, which is a prospective randomized open label trial (in HCV-1-infected subjects with the IL28B CC polymorphism) of treatment with telaprevir (T), peginterferon (P), and ribavirin (R) versus PR alone, will test the working hypothesis. The study design takes advantage of the concept of response-guided treatment, a strategy in which the duration of antiviral treatment is based upon the presence or absence of a rapid virological response (RVR), defined as loss of detectable serum HCV RNA within the first 4 weeks of therapy. In particular, it has been shown that HCV-1 patients who achieve RVR (and maintain undetectable HCV RNA at 12 weeks (defined as eRVR), with either PR-containing or TPR-containing regimens have comparable SVR with 24 weeks, compared with 48 weeks, of total treatment (Mangia 2008, Jacobson 2011).
