16, 17 A majority (80%-90%) of patients
who experienced virological breakthrough or incomplete virological suppression on therapy, or virological relapse after discontinuation of PI therapy, were found to have antiviral resistant variants. In the BOC studies, poor response to interferon (<1 log decline in HCV RNA during the lead-in phase) was associated with a higher rate of development of resistance.12 Among TVR-treated patients, population sequencing has suggested that high-level resistance develops more commonly when virological failure occurs during the initial 12 weeks of treatment, whereas low-level resistance variants are more likely when virological failure occurs later, during treatment with PegIFN and RBV alone. These observations highlight the importance Ulixertinib molecular weight of response to interferon for the prevention of emergence of antiviral resistance. The clinical significance of antiviral resistant variants that emerge during PI therapy is uncertain. In longitudinal follow-up of patients enrolled in phase 2 trials, BOC-resistant variants were detected in 43% of subjects after 2 years of follow-up. Similarly, among patients with documented TVR-resistant variants who were enrolled in the TVR phase 3 trials, 40% still had detectable resistant variants after a median follow-up period of 45 weeks.27 In general, the decline or loss of variants
appears to be related to their level of fitness. Further data are needed to determine whether selection of these variants during and after PI selleck chemical therapy affects subsequent treatment choices. In phase 3 studies, the emergence of resistant variants and virological breakthrough was more common in patients infected with HCV subtype 1a than 1b, a result of a higher genetic barrier required for selection of resistant variants in HCV subtype 1b compared to 1a.28 上海皓元 Thus, HCV subtyping may play a role in helping to select future treatment regimens and predict the development of resistance. Finally, minimizing development of compensatory mutations would involve early discontinuation of PI therapy when antiviral therapy
is unlikely to succeed. Although viral stop rules varied widely in the phase 2 and 3 trials, week 4 and 12 time points on triple therapy are still key decision points for stopping therapy based on HCV RNA levels. Current data suggest that for patients receiving BOC, therapy should be stopped at week 12 if the viral level is >100 IU/mL or >10-15 IU/mL at treatment week 24 and, for TVR, therapy should be stopped at either week 4 or 12 if the viral level is >1,000 IU/mL or if week 24 HCV RNA is detectable. Recommendations: 15. Patients who develop anemia on protease inhibitor-based therapy for chronic hepatitis C should be managed by reducing the ribavirin dose (Class 2a, Level A). The likelihood of achieving an SVR with PegIFN and RBV and of spontaneous resolution of HCV infection differ depending on the nucleotide sequence near the gene for IL28B or lambda interferon 3 on chromosome 19.
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