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Naturally occurring mutations to HCV protease inhibitors in treatment-naïve patients

Stefania Paolucci1, Loretta Fiorina1, Antonio Piralla1, Roberto Gulminetti2, Stefano Novati2, Giorgio Barbarini3, Paolo Sacchi3, Marta Gatti1, Luca Dossena1 and Fausto Baldanti1*

Author Affiliations

1 Molecular Virology Unit, Virology and Microbiology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, 27100, Italy

2 Institute of Infectious Diseases, University of Pavia, Pavia, 27100, Italy

3 Division of Infectious and Tropical Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, 27100, Italy

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Virology Journal 2012, 9:245  doi:10.1186/1743-422X-9-245

Published: 24 October 2012



Protease inhibitors (PIs) to treat hepatitis C (HCV) virus infection have been approved and others are under development.


The aims of this study were to illustrate natural polymorphisms in the HCV protease and measure the frequency of PI resistance mutations in different HCV genotypes from PI-naïve patients.

Direct sequencing of HCV NS3/4A protease was performed in 156 HCV patients naïve to PIs who were infected with genotype 1a (n = 31), 1b (n = 39), 2 (n = 30), 3 (n = 33) and 4 (n = 23).

Amino acid (aa) substitutions associated with HCV PI resistance were found in 17/156 (10.8%) sequences. Mutations V36L, T54S, V55A/I, and Q80K/L were observed in 29% of patients with genotype 1a, and V55F, Q80L/N and M175L in 10% of patients with genotype 1b. The mutation V158M was found in 3% of patients with genotype 2, D168Q was present in 100% of patients with genotype 3 and D168E was observed in 13% of patients with genotype 4. In addition, multiple aa polymorphisms not associated with PI resistance were detected in patients with genotypes 1a, 1b and 4.


Although major PI resistance mutations were not detected, other resistance mutations conferring low level resistance to PIs together with a number of natural polymorphisms were observed in proteases of PI naïve HCV patients. A more extensive analysis is needed to better evaluate the impact of baseline resistance and compensatory mutations in the efficacy of HCV PI treatment.

Hepatitis C virus; HCV baseline resistance; Protease inhibitors; HIV/HCV co-infection; Genetic diversity