Virologic failure during the telaprevir-treatment phase was predominantly associated with higher-level resistance; virologic failure during the peginterferon/ribavirin-treatment phase selleck was associated with higher- or lower-level, or wildtype variants, depending on genotype. Relapse occurred in 9% of patients completing assigned treatment and was generally associated with lower-level resistant variants or wildtype. Resistant variants were no longer detectable by study end (median follow-up of 11 months)

in 58% of non-SVR patients. Conclusion: In REALIZE, variants emerging in non-SVR, telaprevir-treated patients were similar irrespective of the use of a lead-in and were consistent with those previously reported. In most patients, AZD6244 resistant variants became undetectable over time. (HEPATOLOGY 2012;56:2106–2115) Telaprevir is a potent and selective inhibitor of the nonstructural (NS) 3·4A protease of the hepatitis C virus (HCV).1 This direct-acting antiviral (DAA) recently demonstrated significantly higher efficacy over placebo in combination with peginterferon/ribavirin

in randomized Phase 3 trials conducted in patients infected with HCV genotype 1,2-4 and is now approved in the United States and Europe for the treatment of genotype 1 chronic hepatitis in adult patients with compensated liver disease.5, 6 The efficacy of telaprevir-based treatment in patients for whom prior peginterferon/ribavirin therapy had failed was demonstrated in the Phase 3 REALIZE trial, which enrolled prior relapsers, partial responders, and null responders.4

Sustained virologic response (SVR) (undetectable plasma HCV RNA 24 weeks after the last planned administration of a study drug) with telaprevir-based regimens were significantly superior to peginterferon/ribavirin alone across all populations: 86% versus 24% in prior relapsers, 57% versus 15% in prior partial responders, and 31% L-NAME HCl versus 5% in prior null responders.4 Using the definition of HCV RNA <25 IU/mL at last observation within the week 72 visit window, SVR rates were 86% versus 22% in prior relapsers, 59% versus 15% in prior partial responders, and 32% versus 5% in prior null responders.5 No clinical benefit was observed in patients receiving a 4-week peginterferon/ribavirin lead-in before starting triple combination therapy, compared with those initiating all drugs simultaneously. Given the limitations of retreatment with peginterferon/ribavirin in HCV genotype 1-infected patients,7, 8 the HCV protease inhibitors telaprevir4 and boceprevir9 represent an important clinical advance. However, these and other DAAs are associated with new management issues, including the potential for the development of resistance.