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Resistance of Hepatitis C Virus to Inhibitors: Complexity and Clinical Implications.

Perales C, Quer J, Gregori J, Esteban JI, Domingo E - Viruses (2015)

Bottom Line: Selection of inhibitor-resistant viral mutants is universal for viruses that display quasi-species dynamics, and hepatitis C virus (HCV) is no exception.Here we review recent results on drug resistance in HCV, with emphasis on resistance to the newly-developed, directly-acting antiviral agents, as they are increasingly employed in the clinic.Strategies to diminish the probability of viral breakthrough during treatment are briefly outlined.

View Article: PubMed Central - PubMed

Affiliation: Liver Unit, Internal Medicine, Laboratory of Malalties Hepàtiques, Vall d'Hebron Institut de Recerca-Hospital Universitari Vall d'Hebron (VHIR-HUVH), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain. celia.perales@vhir.org.

ABSTRACT
Selection of inhibitor-resistant viral mutants is universal for viruses that display quasi-species dynamics, and hepatitis C virus (HCV) is no exception. Here we review recent results on drug resistance in HCV, with emphasis on resistance to the newly-developed, directly-acting antiviral agents, as they are increasingly employed in the clinic. We put the experimental observations in the context of quasi-species dynamics, in particular what the genetic and phenotypic barriers to resistance mean in terms of exploration of sequence space while HCV replicates in the liver of infected patients or in cell culture. Strategies to diminish the probability of viral breakthrough during treatment are briefly outlined.

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Examples of genetic barrier for generating NS3/4A resistance mutations in HCV. The percentages given for each subtype (1a and 1b) have been calculated with the relevant triplets in a subtype alignment of sequences for GTs 1a and 1b HCV genomic sequences retrieved from [97] with the condition of belonging to full genome sequences, and being devoid of large insertions/deletions (M.E. Soria and C. Perales, unpublished results). The most represented triplets for GTs 1a and 1b are boxed in red; “-“ in the place of a percentage means that the relevant triplet was not represented among the compared sequences. “ts” and “tv” means transition and transversion, respectively. The mutations needed at positions 36 and 155 (resistance to TPV and BOC, among others) are highlighted in red. Data based on several publications quoted in the text.
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viruses-07-02902-f002: Examples of genetic barrier for generating NS3/4A resistance mutations in HCV. The percentages given for each subtype (1a and 1b) have been calculated with the relevant triplets in a subtype alignment of sequences for GTs 1a and 1b HCV genomic sequences retrieved from [97] with the condition of belonging to full genome sequences, and being devoid of large insertions/deletions (M.E. Soria and C. Perales, unpublished results). The most represented triplets for GTs 1a and 1b are boxed in red; “-“ in the place of a percentage means that the relevant triplet was not represented among the compared sequences. “ts” and “tv” means transition and transversion, respectively. The mutations needed at positions 36 and 155 (resistance to TPV and BOC, among others) are highlighted in red. Data based on several publications quoted in the text.

Mentions: Substitution S282T has been selected in vivo in the course of different treatments that included SOF [88,89,90,91,92]. Additional amino acid changes at position 282 (G/C/R) have been related with SOF resistance using in silico models [6], and substitution S282G was also detected in several liver isolates from one patient [93]. HCV offers a direct example of how rapid evolution of a virus in nature and its diversification into GTs and subtypes [94] lead to differences in nucleotide composition that affect the evolutionary pathways towards drug resistance. Several examples of differences in composition of the triplets that encode amino acids in NS3 which participate in inhibitor resistance are given in Figure 2. Such variations can affect the barrier to resistance because of the requirement of either one or two transition or transversion mutations (indicated as ts and tv in Figure 2) to reach the required amino acid. Therefore, virus diversification is, by itself, a source of disparate behavior in terms of inhibitor sensitivities. HCV subtype is a key determinant on the efficacy of DAAs, with subtype 1a patients displaying lower response rates than those infected with subtype 1b [78,95]. A correct subtyping is essential to decide which treatment is the most adequate for each patient and this is now feasible due to NGS technologies [96]. It is still an open question whether resistance to DAAs displaying high barrier to resistance will become a significant clinical issue for treatment failure or not. Experience with other viral diseases suggests that the problem is likely to become relevant. It will largely depend on the management of the new combinations to poorly responding patients—who offer environments that are prone to select for escape mutants—, on the initial fitness capacity of exploration of sequence space for further fitness increases (compare with Section 2), and also on the frequency of transmission of the newly generated mutants.


Resistance of Hepatitis C Virus to Inhibitors: Complexity and Clinical Implications.

Perales C, Quer J, Gregori J, Esteban JI, Domingo E - Viruses (2015)

Examples of genetic barrier for generating NS3/4A resistance mutations in HCV. The percentages given for each subtype (1a and 1b) have been calculated with the relevant triplets in a subtype alignment of sequences for GTs 1a and 1b HCV genomic sequences retrieved from [97] with the condition of belonging to full genome sequences, and being devoid of large insertions/deletions (M.E. Soria and C. Perales, unpublished results). The most represented triplets for GTs 1a and 1b are boxed in red; “-“ in the place of a percentage means that the relevant triplet was not represented among the compared sequences. “ts” and “tv” means transition and transversion, respectively. The mutations needed at positions 36 and 155 (resistance to TPV and BOC, among others) are highlighted in red. Data based on several publications quoted in the text.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4664975&req=5

viruses-07-02902-f002: Examples of genetic barrier for generating NS3/4A resistance mutations in HCV. The percentages given for each subtype (1a and 1b) have been calculated with the relevant triplets in a subtype alignment of sequences for GTs 1a and 1b HCV genomic sequences retrieved from [97] with the condition of belonging to full genome sequences, and being devoid of large insertions/deletions (M.E. Soria and C. Perales, unpublished results). The most represented triplets for GTs 1a and 1b are boxed in red; “-“ in the place of a percentage means that the relevant triplet was not represented among the compared sequences. “ts” and “tv” means transition and transversion, respectively. The mutations needed at positions 36 and 155 (resistance to TPV and BOC, among others) are highlighted in red. Data based on several publications quoted in the text.
Mentions: Substitution S282T has been selected in vivo in the course of different treatments that included SOF [88,89,90,91,92]. Additional amino acid changes at position 282 (G/C/R) have been related with SOF resistance using in silico models [6], and substitution S282G was also detected in several liver isolates from one patient [93]. HCV offers a direct example of how rapid evolution of a virus in nature and its diversification into GTs and subtypes [94] lead to differences in nucleotide composition that affect the evolutionary pathways towards drug resistance. Several examples of differences in composition of the triplets that encode amino acids in NS3 which participate in inhibitor resistance are given in Figure 2. Such variations can affect the barrier to resistance because of the requirement of either one or two transition or transversion mutations (indicated as ts and tv in Figure 2) to reach the required amino acid. Therefore, virus diversification is, by itself, a source of disparate behavior in terms of inhibitor sensitivities. HCV subtype is a key determinant on the efficacy of DAAs, with subtype 1a patients displaying lower response rates than those infected with subtype 1b [78,95]. A correct subtyping is essential to decide which treatment is the most adequate for each patient and this is now feasible due to NGS technologies [96]. It is still an open question whether resistance to DAAs displaying high barrier to resistance will become a significant clinical issue for treatment failure or not. Experience with other viral diseases suggests that the problem is likely to become relevant. It will largely depend on the management of the new combinations to poorly responding patients—who offer environments that are prone to select for escape mutants—, on the initial fitness capacity of exploration of sequence space for further fitness increases (compare with Section 2), and also on the frequency of transmission of the newly generated mutants.

Bottom Line: Selection of inhibitor-resistant viral mutants is universal for viruses that display quasi-species dynamics, and hepatitis C virus (HCV) is no exception.Here we review recent results on drug resistance in HCV, with emphasis on resistance to the newly-developed, directly-acting antiviral agents, as they are increasingly employed in the clinic.Strategies to diminish the probability of viral breakthrough during treatment are briefly outlined.

View Article: PubMed Central - PubMed

Affiliation: Liver Unit, Internal Medicine, Laboratory of Malalties Hepàtiques, Vall d'Hebron Institut de Recerca-Hospital Universitari Vall d'Hebron (VHIR-HUVH), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain. celia.perales@vhir.org.

ABSTRACT
Selection of inhibitor-resistant viral mutants is universal for viruses that display quasi-species dynamics, and hepatitis C virus (HCV) is no exception. Here we review recent results on drug resistance in HCV, with emphasis on resistance to the newly-developed, directly-acting antiviral agents, as they are increasingly employed in the clinic. We put the experimental observations in the context of quasi-species dynamics, in particular what the genetic and phenotypic barriers to resistance mean in terms of exploration of sequence space while HCV replicates in the liver of infected patients or in cell culture. Strategies to diminish the probability of viral breakthrough during treatment are briefly outlined.

Show MeSH
Related in: MedlinePlus