December 17, 2013

Naturally occurring resistance mutations to inhibitors of HCV NS5A region and NS5B polymerase in DAA treatment-naive patients

Virology Journal 2013, 10:355 doi:10.1186/1743-422X-10-355

Stefania Paolucci (
Loretta Fiorina (
Bianca Mariani (
Roberto Gulminetti (
Stefano Novati (
Giorgio Barbarini (
Raffaele Bruno (
Fausto Baldanti (

ISSN 1743-422X

Article type Research
Submission date 23 September 2013
Acceptance date 3 December 2013
Publication date 17 December 2013

Article URL
This peer-reviewed article can be downloaded, printed and distributed freely for any purposes (see
copyright notice below).

Articles in Virology Journal are listed in PubMed and archived at PubMed Central.

For information about publishing your research in Virology Journal or any BioMed Central journal, go

For information about other BioMed Central publications go to



Direct-acting antiviral (DAA) agents target HCV proteins; some of these have already been approved for the treatment of HCV infection, while others are in development. However, selection of DAA-resistant viral variants may hamper treatment. The aim of this study was to illustrate potential natural DAA-resistance mutations in the HCV NS5A and NS5B regions of HCV genotypes 1a and 1b from DAA-naïve patients.


Direct sequencing of HCV NS5A and NS5B regions was performed in 32 patients infected with HCV genotype 1a and 30 patients infected with HCV genotype 1b; all subjects were naïve to DAAs.


In genotype 1a strains, resistance mutations in NS5A (M28V, L31M and H58P) were observed in 4/32 (12.5%) patients, and resistance mutations in NS5B (V321I, M426L, Y448H, Y452H) were observed in 4/32 (12.5%) patients. In genotype 1b, resistance mutations in NS5A (L28V, L31M, Q54H, Y93H and I280V) were observed in 16/30 (53.3%) patients, while resistance mutations in NS5B (L159F, V321I, C316N, M426L, Y452H, R465G and V499A) were observed in 27/30 (90%) patients.


Mutations conferring DAA resistance were detected in NS5A and NS5B of HCV genotypes 1a and 1b from DAA-naïve patients. Although some mutations confer only a low level of resistance, the presence at baseline of mutated HCV variants should be taken into consideration in the context of DAA therapy.

Keywords Hepatitis C virus, HCV baseline resistance, NS5A and NS5B genes, DAA inhibitors


Hepatitis C virus (HCV) is classified into six genotypes (1–6) and more than 100 subtypes. The most common genotypes in Western countries are 1a and 1b [1]. Peginterferon/ribavirin (PegIFN/RBV) for the treatment of HCV infection is burdened by adverse reactions in at least 10% of patients [2]. Moreover, a sustained virological response is achieved in only 50% of patients infected with HCV genotype 1 [3]. PegIFN/RBV treatment failure is mainly attributed to its low efficacy against genotypes 1 and 4, but also, to some extent to its side effects [3,4]. Recently developed direct-acting antiviral agents (DAAs) are predicted to have a major impact both in combination with PegIFN/RBV, as well as in IFN-free regimens and telaprevir and boceprevir have now been approved as standard of care treatment [5]. Targets for DAA include HCV NS3 protease, NS5B polymerase and NS5A protein which are essential for virus replication. [6-12].

Nevertheless, the combination of a high HCV replication rate, the low fidelity of HCV polymerase and selective pressures by the immune system and drug treatment lead to the in vivo development of viral quasispecies with high sequence diversity among various genotypes and subtypes [13,14] with the potential accumulation of virus variants showing mutations with varying degrees of resistance to DAAs [11-13,15-22], even in the absence of pre-existing drug-exposure [17,23-26]. In particular, natural changes in HCV NS5A and NS5B amino acids (aa) associated with reduced drug susceptibility have been observed in treatment naïve patients [17,27,28].

Continue reading full article (PDF) here – [Free]

No comments:

Post a Comment