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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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Related in: MedlinePlus

Directly acting antivirals currently available for treatment of hepatitis C virus. Inhibitors target the NS3/4A protease, the non-structural protein NS5A, and the viral polymerase NS5B. Boxes indicate new oral IFN-free combinations.
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viruses-07-02902-f001: Directly acting antivirals currently available for treatment of hepatitis C virus. Inhibitors target the NS3/4A protease, the non-structural protein NS5A, and the viral polymerase NS5B. Boxes indicate new oral IFN-free combinations.

Mentions: Since 2011, a new generation of anti-HCV agents, termed Directly-Acting Antivirals (or DAAs) entered the picture of anti-HCV therapy, resulting in great improvement of SVR rates. These new inhibitors target the NS3/4A protease, the non-structural protein NS5A or the viral polymerase NS5B [66,67]. With the introduction of the first-generation HCV NS3/4A protease inhibitors (PI), telaprevir (TPV), and boceprevir (BOC), which are given in combination with pegIFN + RBV, the SVR rates have significantly increased by more than 30%. However, in 20% to 40% of patients, treatment fails and viral load reappears either during therapy (“breakthrough”), or upon treatment interruption (“relapse”). More recently, the approval of new DAAs, such as simeprevir (directed to NS3/4A), daclatasvir (DCV)(directed to NS5A), and sofosbuvir (SOF)(directed to NS5B), as well as oral IFN-free combinations such as ledipasvir/SOF (Harvoni) (directed to NS5A and NS5B, respectively) and triple therapy paritaprevir/ritonavir + ombitasvir + dasabuvir (Viekirax and Exviera) (directed to NS3, NS5A, and NS5B, respectively) have increased the SVR rate to more than 90% in clinical trials with treatment-naïve and cirrhotic patients [67,68,69,70,71,72] (Figure 1).


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

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

Directly acting antivirals currently available for treatment of hepatitis C virus. Inhibitors target the NS3/4A protease, the non-structural protein NS5A, and the viral polymerase NS5B. Boxes indicate new oral IFN-free combinations.
© Copyright Policy
Related In: Results  -  Collection

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

viruses-07-02902-f001: Directly acting antivirals currently available for treatment of hepatitis C virus. Inhibitors target the NS3/4A protease, the non-structural protein NS5A, and the viral polymerase NS5B. Boxes indicate new oral IFN-free combinations.
Mentions: Since 2011, a new generation of anti-HCV agents, termed Directly-Acting Antivirals (or DAAs) entered the picture of anti-HCV therapy, resulting in great improvement of SVR rates. These new inhibitors target the NS3/4A protease, the non-structural protein NS5A or the viral polymerase NS5B [66,67]. With the introduction of the first-generation HCV NS3/4A protease inhibitors (PI), telaprevir (TPV), and boceprevir (BOC), which are given in combination with pegIFN + RBV, the SVR rates have significantly increased by more than 30%. However, in 20% to 40% of patients, treatment fails and viral load reappears either during therapy (“breakthrough”), or upon treatment interruption (“relapse”). More recently, the approval of new DAAs, such as simeprevir (directed to NS3/4A), daclatasvir (DCV)(directed to NS5A), and sofosbuvir (SOF)(directed to NS5B), as well as oral IFN-free combinations such as ledipasvir/SOF (Harvoni) (directed to NS5A and NS5B, respectively) and triple therapy paritaprevir/ritonavir + ombitasvir + dasabuvir (Viekirax and Exviera) (directed to NS3, NS5A, and NS5B, respectively) have increased the SVR rate to more than 90% in clinical trials with treatment-naïve and cirrhotic patients [67,68,69,70,71,72] (Figure 1).

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