This study showed that patients undergoing PEG-IFN, ribavirin, and telaprevir triple therapy for chronic hepatitis C genotype 1 infection achieve a higher SVR rate than typically expected under combination therapy alone in Japanese patients. Moreover, patients who showed transient response in previous treatment were more likely to achieve SVR after triple therapy, whereas nonresponders to prior treatment remained unlikely to eradicate the virus. Considering that telaprevir has a mode of action different from that of IFN and ribavirin, [5
] it is surprising that triple therapy does not better improve SVR rates among prior nonresponders, suggesting that additional unknown factors contribute to nonresponse. However, the duration of triple therapy, followed by standard of care, was limited to 24 weeks in this study; therefore, it is possible that prior nonresponders and patients who experienced relapse may benefit from a longer duration of therapy.
The most interesting result from this study is the high SVR rate among patients who previously experienced relapse, even compared with that of naive patients. This is partly because of the higher frequency of the favorable rs8099917 TT genotype among patients who previously experienced relapse (33 [75%] of 44) than among naive patients (15 [60%] of 25), which perhaps reflects the fact that all patients who previously experienced relapse demonstrated at least a transient response to combination therapy and that this group is less likely to include as many patients with non-TT genotypes. All of the treatment-naive patients with the favorable genotype (15 [100%] of 15) achieved SVR, compared with 31 (94%) of 33 patients who previously experienced relapse; conversely, only one-half of the treatment-naive patients with unfavorable rs8099917 genotypes (5 [50%] of 10) achieved SVR, compared with only 1 (9%) of 11 of the patients who previously experienced relapse. This suggests that, although patients who previously experienced relapse have a demonstrated potential to respond to the therapy, there should be more variability among naive patients. Another consideration is that the frequency of the favorable wild-type core70 amino acid was slightly higher among patients who previously experienced relapse (28 [64%] of 44) than among naive patients (13 [52%] of 25). It should be noted, however, that the small number of patients in this study limits the conclusions that can be drawn, and results should be verified in a larger study, perhaps using stratified sampling based on patient background with regard to treatment history to establish more homogeneous patient populations.
In this and a number of other studies, variation in the IL28B locus remains the strongest predictor of SVR reported to date [16
]. It is unclear which, if any, of the reported SNPs is the primary or functional SNP, but most studies report results for rs8099917 and/or rs12979860, which are under strong linkage disequilibrium in Japanese patients and fall within the intergenic region upstream of IL28B. Although the mechanism is unknown, IL28B and the other 2 members of the IFN-λ family, IL28A and IL29, code for type III IFNs, which are similar to type I IFNs but use a highly tissue-specific receptor [36
]. IFN-stimulated genes appear to be initially down-regulated in patients with the favorable rs8099917 TT genotype [38
], which may help to prevent desensitization and promote maximal induction of IFN-stimulated genes, although mechanistic studies are needed to understand the connection between IL28B and SVR.
In addition to IL28B polymorphisms, a number of studies have reported that amino acid substitutions in the HCV core protein and the ISDR region of NS5A independently predict treatment outcome after combination therapy [14
], and these findings have recently been extended to triple therapy[39
]. In this study, substitution at core70 was significant in univariate tests and was selected for inclusion in the multivariate model, but it was not significant in multiple logistic regression. One reason for this may be that core substitutions were initially reported to be associated with nonresponse [22
], whereas this study focused on SVR because of the very small number of nonresponders. Terms that are significant in univariate but not multivariate tests may be correlated with each other, and only the factor with the strongest effect remains significant. In this case, core70 is significantly correlated with the stronger rs8099917 genotype (r
= .31; P
= .0027), although other studies have shown that these terms contribute independently, especially when a larger number of patients are included [39
]. Without knowing the mechanism underlying either factor, it is not possible to determine whether the underlying factors that they represent are in fact independent or whether they represent different aspects of a common unknown factor.
Although novel therapies that are not based on IFN and ribavirin are urgently needed, the pending introduction of protease inhibitors represents a pivotal addition to the treatment arsenal, especially for patients who show at least partial response to combination therapy. Because telaprevir is effective as monotherapy, even if only briefly until resistant mutations emerge, alternate combination therapies based on telaprevir and another component designed to raise the barrier to resistance may provide an adequate alternative for older patients and patients unable to tolerate IFN or ribavirin. Furthermore, identification of additional SNPs associated with anemia and other adverse effects will help reduce complications and the need for dose reductions and may lead to treatment guidelines for at-risk patients, such as administration of erythropoietin to stimulate erythropoiesis [41
]. Ribavirin dose reductions were required significantly earlier in patients with ITPA SNP genotype CC, compared with patients with non-CC genotypes, which may contribute to poorer response if cumulative ribavirin administration decreases to <80% of the planned dose [26
], although ribavirin dose reduction did not affect SVR rate in this study.
In conclusion, triple therapy with PEG-IFN, ribavirin, and telaprevir resulted in higher rates of SVR, compared with PEG-IFN plus ribavirin combination therapy, especially among treatment-naive patients and patients who showed transient response to prior treatment. ITPA polymorphisms predict ribavirin-induced anemia but are not associated with SVR, whereas IL28B polymorphisms and early viral kinetics remain the strongest predictors of SVR with use of triple therapy. Considering both host and viral factors, we identified 2 subgroups of patients who responded well to triple therapy: patients with the favorable rs8099917 TT genotype (47 [94%] of 50) and patients with non-TT genotypes who had wild-type core70 and core91 amino acids (7 [78%] of 9). Patients matching these conditions would benefit most from this 24-week triple therapy, whereas a longer duration of therapy should perhaps be considered for the remaining difficult-to-treat patients.