Editorial

Chronic carriers of the hepatitis C virus (HCV) constitute a huge reservoir of cirrhosis and hepatocellular carcinoma which, ultimately, are a growing cause of liver-related mortality worldwide [1]. Treatment with pegylated interferon (PegIFN) combined with ribavirin (Rbv) is the only option for preventing HCV-related end stage liver disease. Currently, sustained virological response (SVR) rates, the surrogate definition of a cure of the disease, of up to 90% are achievable in patients infected with HCV genotypes 2 and 3, but the SVR rate is about 50% for patients infected with HCV genotype 1, the most common form [2]. Therefore, patients infected with HCV genotypes 1 and 4 who fail to respond to IFN-based therapies represent a very important unmet clinical need in the HCV arena, as highlighted also by the unsatisfactory success rate of re-treatment with Peg IFN/Rbv [3,4]. Therefore, it was with understandably great anticipation that hepatologists awaited the final reports on triple therapy with the orally bio-available protease inhibitors (PI) telaprevir and boceprevir, known to improve SVR rates to 75% in this difficult-to-cure population [5,6]. Even more welcomed were the final reports of the Prove 3 (telaprevir) and Respond 2 (boceprevir) studies, which demonstrated that re-treatment of relapsing or nonresponding HCV genotype 1 infections with standard therapy plus a PI significantly increases the likelihood of HCV eradication [7,8]. Now that we have confirmation that the new direct-acting antiviral agents will provide a major breakthrough in the treatment of patients with HCV genotype 1 infections, although at the cost of increased treatment-related side effects and discontinuation rates, we must adopt new therapeutic algorithms based on careful pretreatment patient stratification. This purpose might be served by the recent description of a set of polymorphisms in the interleukin 28B (IL28B) gene region, which encodes interferon k3 and is associated with response to Peg IFN/Rbv therapy in HCV patients [9,10]. In fact, the link between IL28B genotype and treatment outcome might allow for pretreatment stratification aimed at refining not only decisions regarding the initiation of current therapy, but also the design of clinical trials with new direct antiviral agents. Indeed, it is worthwhile to test both a strategy restricting dual therapy to patients with the favourable IL28B genotype (CC), while administering triple therapy to those with unfavourable genotypes (TT or CT), and also a strategy in which patients are stratified by IL28B genotype for dosing and duration of antiviral therapy. This strategy might be even more cost-effective once second wave direct antiviral agents, endowed with higher genetic barriers and broader antiviral activity against different HCV genotypes, become available. Indeed, we should acknowledge that the applicability of first generation antivirals is jeopardized by a very high risk of generating resistant HCV mutants with variable degrees of replicative fitness and by low tolerability, which could translate into higher rates of treatment discontinuation compared to dual therapy with PegIFN/Rbv alone [11]. Cutaneous rash, pruritus and anaemia following telaprevir versus anaemia and disgeusia following boceprevir were more common in the triple regimen than in the standard of care groups. Undoubtedly, the management and treatment of patients with chronic HCV infection will become more complicated, requiring increased scientific and clinical expertise to meet the new challenges that this first generation of direct-acting antivirals will provide. Although the development of viral resistance to PIs occurs in a minority of patients receiving the triple therapy regimens, it is important to outline that those mutant strains will likely preclude or delay our patients from receiving other class-specific direct antiviral agents [12]. Because alternative anti-HCV agents such as nucleoside or nonnucleoside NS5B polymerase inhibitors are in the early stages of development, patients with resistant disease will be left waiting for future drugs to enter the market before an effective anti-HCV regimen can be started. Thus, when a patient is considered for treatment with PIs, a careful risk/benefit evaluation must be conducted at the individual level; careful patient selection for triple therapy is mandatory. This is even more important when re-treating patients with genotype-1 infections, where breakthrough rates are higher among nonresponders (particularly those with < 1 log decline of HCV-RNA at week 4 of treatment) than among relapsers and among patients infected with subtype 1a compared with subtype 1b. The clinical implication of these observations is clear: PIs require some degree of viral response to PegIFN and Rbv to maximize their antiviral activity, therefore suggesting that treatment be prioritized in relapsing patients and in those primary nonresponders experiencing a ‡1 log decline in HCV-RNA at week 4 of lead in treatment with PegIFN+Rbv. In addition, an updating of HCV genotype definition is mandatory to avoid false positive diagnosis of 1b using tests based on sequence analysis or reverse hybridization of only the 5¢ noncoding region of HCV, a risk that can be avoided using a second generation reverse hybridization assay that targets both the 5¢ noncoding and the core-coding region of HCV [13]. Last but not least, the landscape of therapeutic effectiveness needs to be reshaped in terms of reducing HCV-related mortality at the population level. Given that HCV-related mortality in the general population can only be Journal of Viral Hepatitis, 2012, 19 (Suppl. 1), 1–2 doi:10.1111/j.1365-2893.2011.01520.x