For example, viral clearance may have reduced PD-1 expression, thus allowing for recovery of the immune system. In addition, in vitro studies by Foy et al.[22] have shown that NS3 protease inhibitors lead to inhibition of HCV NS3/4A-mediated repression of interferon response factor (IRF3) activation, thus leading to restoration of transcription of interferon-inducible

genes. For 50% (2/4) of those patients who eventually failed rescue, higher-level resistance variants or more fit NS3 resistance variants emerged but the NS5A variants remained unchanged. In a Japanese study assessing the efficacy of daclatasvir and asunaprevir in HCV GT1b patients who were peginterferon-alfa/ribavirin ineligible or intolerant, the combination of suboptimal trough concentrations of both of these agents in plasma, as well as the preexistence of the resistance polymorphism NS5A-Y93H at baseline, may have played a role in patients experiencing Seliciclib virologic breakthrough.[23] In the study described herein, no clear relationship was observed between trough

concentration values of daclatasvir and asunaprevir in the dual regimen and the ability of a patient infected with GT1a to achieve SVR. All but one of the HCV GT1a patients who experienced viral breakthrough were adherent. No baseline NS3 or NS5A resistance variants were detected by clonal analysis, even in the PLX3397 in vitro patient (Patient 1, Fig. 2) who experienced rapid viral breakthrough within the first 2 weeks of treatment. Taken together, the influence of drug exposure on emergence of resistance was difficult to ascertain from this small study examining HCV GT1a failures. As anticipated from a prior null responder population, the majority

of patients in this study carried a non-CC IL28B genotype, thus making a correlation between IL28B status and efficacy hard to assess. Studies in treatment-naive patients would be better suited to examine this relationship. Viral fitness of emergent or enriched NS5A and MCE公司 NS3 variants was dependent on the variant and target. For three of four patients who experienced viral breakthrough and later failed treatment intensification with peginterferon alfa-2a and ribavirin, asunaprevir-resistant variants D168V or D168Y were detected at the time of virologic failure to dual therapy. The D168 resistance variants were no longer detected by clonal analysis 48 weeks posttreatment in these three patients. However, emergent NS3-D168E persisted in one patient. This is not surprising, given that D168E has been detected in treatment-naive patients,[10] suggesting that it is relatively fit. In contrast, emergent daclatasvir-resistant variants persisted throughout 48-week posttreatment. Different NS5A variants (Y93N, L31V-H58P, Q30R-L31M, and L31V-Y93C) were detected in four patients who experienced virologic failure to dual treatment, and all were fit relative to wild-type virus.