Boceprevir (BOC) and telaprevir (TPV) are direct acting antiviral agents that target the protease of the hepatitis C virus (HCV). In combination with pegylated interferon (PEG) and ribavirin (RBV) they increase the effectiveness of antiviral therapy in naïve patients infected with genotype 1 resulting in an increase in sustained virological response (SVR) from around 40% to nearly 70% or more [1, 2]. The major disadvantages of protease inhibitors (PIs) are the possible development of viral resistance (which may be long lasting and reduce future treatment options) and a range of side effects. Furthermore, PIs are expensive and substantially increase the overall cost of therapy. Therefore, while triple therapy is now the standard of care for treatment of genotype 1 patients , we will discuss whether dual therapy with PEG-IFN/RBV has still a place and in which subgroup of patients.
Predictors of response to PEG-IFN/RBV
The factors favouring response to PEG/RBV have been well-identified. In treatment-naïve patients with genotype 1, they are mainly age (<40 years), viral load (<600 000 IU/ml), absence of severe fibrosis and absence of insulin resistance . Nucleotide polymorphisms on chromosome 19 upstream of the interleukin 28B (IL28B) gene have been found to be strongly associated with SVR [5, 6]. The statistical weight of this parameter appears to be similar to that of viral genotype. In CC homozygotes (rs12979860) of Caucasian origin (around 30% of patients) without severe fibrosis, the percentage of SVR was estimated to be 86% vs 36% and 43% for genotypes TT and CT respectively . Analysis of viral kinetics indicated that a rapid virological response (RVR) was obtained in 30% of CC patients vs 5% of CT or TT patients. Therefore, around 80% of patients that achieved a RVR were CC homozygotes. The chance of achieving a SVR in patients achieving a RVR was greater than 90%, regardless of IL28B genotype. In contrast, in CC homozygotes who do not achieve a RVR the probability of achieving a SVR was only 60% . Thus, by considering IL28B genotype and virological response at week 4 it is possible to identify a subgroup of patients with mild fibrosis in whom PEG-IFN/RBV therapy results in a SVR in 90% and in whom triple therapy would probably not be more effective. It is interesting to note that in this group, triple therapy can be shortened from 48 weeks to 24 or 28 weeks.
PEG-IFN/RBV in patients with low viral load and rapid virological response
In patients with low baseline viral load (<400 000 IU/ml) who achieve RVR, a short course (24 weeks) of PEG-IFN/RBV therapy is sufficient to obtain a SVR . In these patients, PEG-IFN/RBV is still clearly the best option. Accordingly, French guidelines have recommended that PEG-IFN/RBV therapy should be considered the first-line treatment in treatment-naive genotype 1 patients with predictive factors for a good response to treatment . A recently published trial has confirmed these recommendations . In 233 treatment-naïve patients with HCV genotype1 without cirrhosis and with a low baseline viral load (<600 000 IU/ml) who are treated with PEG-IFN/RBV lead-in therapy, 101 (48%) with a RVR were randomized to 20 weeks of additional therapy with PEG-IFN/RBV or to 24 weeks of PEG-IFN/RBV/BOC. The rate of SVR was similar in both groups (88% vs 90%), regardless of viral subtype, IL28B or ethnicity. Safety was also similar for side effects, rates of dose reduction (33% vs 33%) or discontinuation (8% vs 6%). These results indicate that adding PI does not change the duration of therapy or efficacy of treatment in treatment naïve patients without cirrhosis with a low baseline viral load who achieve RVR.
PEG-IFN/RBV in treatment-experienced patients ?
Triple therapy is clearly the standard of care in treatment-experienced patients [3, 9]. However, PEG-IFN/RBV can be a therapeutic option in some patients with a resistant variant in whom PI treatment has failed. We reported the case of a patient who relapsed after a 12 week course of TPV-based triple therapy and who was cured by a 48 week-course of dual therapy despite the presence of a resistant variant . While waiting for new molecules retreatment with reinforced regimen of PEG-IFN/RBV could be a therapeutic option in genotype 1-naïve patients who relapse after PI-based triple therapy.