Hepatitis C virus (HCV) infection, the leading cause of cirrhosis, hepatocellular carcinoma (HCC), liver decompensation and indication for liver transplantation affects approximately 170 million people worldwide. Combination therapy of pegylated interferon (PEG-IFN) plus ribavirin (RBV) can achieve an overall sustained virologic response (SVR) rate of 42-46%, 76-82% and 50-77% in chronic hepatitis C (CHC) patients infected with genotype 1, 2 or 3 and 4, respectively. Furthermore, East Asian patients have higher SVR rates for patients with HCV genotype 1 infection than Western patients and comparable rates for genotype 2 infection. Recently, adding direct acting antivirals (DAAs) to PEG-IFN plus RBV further increases the SVR rates to 63-75% and 59-66% in untreated and treatment-experienced Western patients with HCV genotype 1 infection, respectively. However, the previous standard of care for CHC patients is expensive, only effective in a certain proportion of CHC patients, and has many unpleasant adverse effects. Thus, identifying predictive factors for therapeutic response in CHC patients is clinically important in terms of increasing efficacy, avoiding unnecessary side effects, and saving costs.
In late 2009 and early 2010, several genome-wide association studies (GWAS) from different parts of the world indicated that single nucleotide polymorphisms (SNPs) near the interleukin 28B (IL28B) gene (rs12979860 and rs8099917), which is located on chromosome 19 and encodes IFN λ-3, are highly associated with spontaneous or treatment-induced viral clearance in HCV patients. Furthermore, the different allele frequencies among various ethnicities may explain the different viral responses to IFN-based therapies in previous clinical observations, especially in patients with HCV genotype 1 infection. Subsequent studies also suggested that the favorable IL28B SNPs are associated with early viral decline in patients infected with HCV genotype 1/4 and genotype 2/3, which is the key determinant for SVR. While the SVR rates are similar in HCV genotype 1 patients with different IL28B SNPs if they achieve rapid viral response (RVR), the IL28B SNPs play a major role in determining SVR in those who fail to achieve RVR. In contrast, IL28B SNPs does not affect the SVR rates in HCV genotype 2/3 patients treated with 24-week PEG-IFN plus RBV. However, if HCV genotype 2/3 patients receive variable duration of therapy on the basis of RVR results (response-guided therapy, RGT), IL28B SNPs only affect SVR rates in those who fail to achieve RVR.
Although the previous standard of care can cure a significant proportion of CHC patients, the therapeutic efficacy is still not satisfactory, especially for HCV genotype 1 patients with unfavorable genetic variations near the host IL28B gene and on-treatment viral kinetics. Therefore, more effective, tolerable and tailored regimens are required to cure more CHC patients. The recent advances made in unravelling the HCV life cycle as well as the genome structure and in developing HCV replicons as well as infectious viral particles in tissue culture systems have enabled the design of therapeutic agents that directly and specifically inhibit HCV replication. These new direct acting antivirals (DAAs) and host targeted antivirals (HTA) have been developed to improve the virologic response rates to the previous standard of care and may potentially shorten the duration of therapy. At the time of writing, drugs targeting inhibition of the HCV protease complex (NS3/4A protease) and the HCV polymerase complex (NS5B and NS5A) are the most successful. Although more than 90 protease or polymerase inhibitors have entered clinical trials over the past 5 years, many of them were withdrawn from further investigation because of toxicity (e.g. BILN2061, HCV 796, NM283, R1626) or lack of efficacy. Two leading protease inhibitors, telaprevir and boceprevir, have shown promising phase III trial results for HCV genotype 1 patients and have been approved for clinical use in 2011.
To further address these clinically important advances, this issue of Hot Topics in Viral Hepatitis contains four articles by several leading experts in the field. In the first article, Lisker-Melman review and discuss the results of five pivotal phase III clinical trials on protease inhibitors, telaprevir and boceprevir, including SPRINT-2, ADVANCE, ILLUMINATE, RESPOND-2 and REALIZE. All the results demonstrated that add-on DAAs can increase SVR rates, shorten treatment duration, and improve treatment outcomes in difficult-to-treat CHC patients. However, the price of such benefits consists of the increased burden of adverse effects and medical expenditure. In the second article, Cooksley et al. raised the issue of whether add-on DAAs could improve treatment outcomes in CHC patients infected with HCV genotypes 2, 3 and 4, because the SVR to previous standard of care is already 80% and the potential benefits are more limited. Current lines of evidence based on small-scale studies showed that many such patients did not respond well to telaprevir (HCV genotype 2/4) or boceprevir (HCV genotype 2/3), and viral resistance may be an emerging problem. The second-generation protease inhibitors, polymerase inhibitors and cyclophilin inhibitor may have better antiviral activity in vitro but still need to be validated in clinical trials. In the third article, Sarrazin et al. discuss the shifting paradigm in HCV treatment, from current triple therapy to interferon-sparing or interferon-free regimens and quadruple therapy. To achieve this goal, at least two DAAs with at least one molecule with a high genetic barrier to drug resistance should be combined for an interferon-free regimen. Furthermore, the first promising data about the potency of quadruple therapies with two DAAs, PEG-IFN-α and RBV were presented. The last but not the least article, Aghemo et al. describe how the IL28B genotype was discovered and why IL28B genotypes influence treatment outcomes in CHC patients. In addition, the usefulness of IL28B genotype as a predictor of treatment efficacy and its impact on on-treatment viral kinetics in both HCV genotype 1 and non-1 patients are discussed in detail. Finally, the authors suggested that although IL28B testing should be incorporated into the pre-treatment algorithm for HCV genotype 1/4 patients, treatment decisions should never be based on this predictor alone.
It is known that the higher SVR rates to PEG-IFN plus RBV therapy in Asian patients compared to Western patients can be partly explained by the fact that Asian patients have a higher frequency of favorable IL28B gene SNPs than Western patients. With this inherent advantage, Asian treatment-naïve HCV genotype 1 patients treated with 24-week triple therapy of DAA in combination with PEG-IFN plus RBV are expected to have an even higher SVR rate of 90%. In addition, we may identify patients who can benefit from a truncated 12-week triple therapy by using baseline host/virus factors and on-treatment viral responses. For easy-to-treat patients such as those with HCV genotype 2 infection, IFN-free regimen with combinations of DAAs or HTA may be feasible. All of these speculations should be further investigated by large-scale clinical trials in the Asia-Pacific region. However, drug resistance, more adverse events and increased medical cost are likely to be the new treatment barriers in the Asia-Pacific region.
The number of baseline and on-treatment predictors is on the increase, and several important predictors have been identified in recent years. With these advances, personalized treatment for CHC is no longer a remote or impossible issue in the foreseeable future.