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First-generation protease inhibitors: where are we now?
The first-generation protease inhibitors (PIs) of hepatitis C virus (HCV), telaprevir and boceprevir, are the harbingers of important advances in the treatment of chronic HCV infection. Improved response rates have been observed in both previously untreated and previously treated patients who have failed pegylated interferon (PEG-IFN) and ribavirin (RBV) treatment.1–5 Sustained virological response (SVR) rates of >70% have been reported. Despite the side effects of the agents and their continued necessity for a PEG-IFN and RBV backbone, the high rates of early viral response translate into higher rates of cure than with PEG-IFN and RBV alone in genotype 1 infection. Their efficacy in the treatment of genotype 2–6 has not been fully tested.6 Activity in in vitro cell culture systems showed similar efficacy of PIs against genotypes 2a, 5a and 6a and comparatively low but varying efficacy against genotype 3a isolates.7 Replication-competent intergenotype chimaeras inserted into the JFH clone of HCV have shown susceptibility to telaprevir, with genotypes 1 and 2 being most susceptible and genotypes 4 and 5 most resistant.8
Previously untreated (naïve) patients without severe fibrosis respond better to the first-generation PIs than those with advanced fibrosis or cirrhosis. Although response rates in patients with cirrhosis are improved compared with PEG-IFN and RBV treatment, they remain suboptimal. Patients with a prior null response (defined as a decline in HCV RNA of <2 log10 after 12 weeks of treatment) and cirrhosis are less likely to respond to retreatment with telaprevir or boceprevir.9 ,10 Approximately 15% of prior null responders and cirrhosis respond to first-generation PIs, and only 35% of those with a prior partial response and cirrhosis respond to retreatment. Inherited IL28b haplotypes continue to influence response rates.11 ,12 Response rates are slightly lower in subtype 1a compared with subtype 1b.