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Host-Targeting Agents to Prevent and Cure Hepatitis C Virus Infection.

Zeisel MB, Crouchet E, Baumert TF, Schuster C - Viruses (2015)

Bottom Line: In contrast to DAAs that target viral proteins, host-targeting agents (HTAs) interfere with cellular factors involved in the viral life cycle.By acting through a complementary mechanism of action and by exhibiting a generally higher barrier to resistance, HTAs offer a prospective option to prevent and treat viral resistance.Indeed, given their complementary mechanism of action, HTAs and DAAs can act in a synergistic manner to reduce viral loads.

View Article: PubMed Central - PubMed

Affiliation: Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France. mirjam.zeisel@unistra.fr.

ABSTRACT
Chronic hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma (HCC) which are leading indications of liver transplantation (LT). To date, there is no vaccine to prevent HCV infection and LT is invariably followed by infection of the liver graft. Within the past years, direct-acting antivirals (DAAs) have had a major impact on the management of chronic hepatitis C, which has become a curable disease in the majority of DAA-treated patients. In contrast to DAAs that target viral proteins, host-targeting agents (HTAs) interfere with cellular factors involved in the viral life cycle. By acting through a complementary mechanism of action and by exhibiting a generally higher barrier to resistance, HTAs offer a prospective option to prevent and treat viral resistance. Indeed, given their complementary mechanism of action, HTAs and DAAs can act in a synergistic manner to reduce viral loads. This review summarizes the different classes of HTAs against HCV infection that are in preclinical or clinical development and highlights their potential to prevent HCV infection, e.g., following LT, and to tailor combination treatments to cure chronic HCV infection.

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Related in: MedlinePlus

Synergy between HTAs and DAAs to inhibit HCV infection at different steps of the viral life cycle. Given their complementary mechanism of action, HTAs and DAAs can act in a synergistic manner to reduce viral loads and to prevent viral resistance. Different classes of HTAs and DAAs that have been evaluated in combination are highlighted in red.
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viruses-07-02898-f004: Synergy between HTAs and DAAs to inhibit HCV infection at different steps of the viral life cycle. Given their complementary mechanism of action, HTAs and DAAs can act in a synergistic manner to reduce viral loads and to prevent viral resistance. Different classes of HTAs and DAAs that have been evaluated in combination are highlighted in red.

Mentions: Given that they target a highly variable virus, the main limitation of DAAs is viral resistance. Viral resistance may be prevented using different strategies including (i) targeting conserved viral sequences less prone to mutation; (ii) using a combination of drugs exhibiting distinct targets and mechanisms of action; and (iii) increasing host antiviral responses. In contrast to the first DAAs, the emergence of viral resistance with recently approved DAAs, such as sofosbuvir, is less frequent but has nevertheless been described [2,243,244,245]. Given the generally lower barrier to resistance of DAAs as compared to HTAs, the emergence of treatment-resistant viral variants during DAA therapy remains a challenge. By acting through a complementary mechanism of action and by exhibiting a generally higher barrier to resistance, HTAs can be associated with DAAs to prevent viral resistance. Indeed, given their complementary mechanism of action, HTAs and DAAs can act in a synergistic manner to reduce viral loads [13,21,103] (Figure 4). Interestingly, various HTAs may also be combined to synergistically inhibit HCV infection, as demonstrated for combinations of a HTEI and host-targeting replication inhibitor, i.e., a Cyp inhibitor [21]. Furthermore, HTEIs have been demonstrated to prolong viral suppression by DAAs and to prevent viral dissemination of DAA-resistant strains in vitro [21,246,247]. Indeed, although treatment of HCV-infected cells with DAAs rapidly results in a dramatic reduction of viral load in vitro, viral rebound is usually observed following withdrawal of the drug. However, the addition of an HTEI to the cell culture at the time of DAA withdrawal allows the further decrease of the viral load, indicating that HTEIs limit viral rebound from DAA therapy [21,246]. Furthermore, as many HTEIs inhibit cell-to-cell transmission that has been shown to represent the major route of transmission of wild type and DAA-resistant viruses, HTEIs have been demonstrated to limit dissemination of DAA-resistant strains and consequently prevent antiviral resistance [247]. In line with these in vitro data, the Cyp inhibitor alisporivir, currently in phase 2/3 clinical trials, has been shown to efficiently reduce viral loads in chronic hepatitis C patients in combination with ribavirin [32] and future clinical trials evaluating its antiviral effect in combination with DAAs will provide further insights into the potential of this HTA.


Host-Targeting Agents to Prevent and Cure Hepatitis C Virus Infection.

Zeisel MB, Crouchet E, Baumert TF, Schuster C - Viruses (2015)

Synergy between HTAs and DAAs to inhibit HCV infection at different steps of the viral life cycle. Given their complementary mechanism of action, HTAs and DAAs can act in a synergistic manner to reduce viral loads and to prevent viral resistance. Different classes of HTAs and DAAs that have been evaluated in combination are highlighted in red.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4664971&req=5

viruses-07-02898-f004: Synergy between HTAs and DAAs to inhibit HCV infection at different steps of the viral life cycle. Given their complementary mechanism of action, HTAs and DAAs can act in a synergistic manner to reduce viral loads and to prevent viral resistance. Different classes of HTAs and DAAs that have been evaluated in combination are highlighted in red.
Mentions: Given that they target a highly variable virus, the main limitation of DAAs is viral resistance. Viral resistance may be prevented using different strategies including (i) targeting conserved viral sequences less prone to mutation; (ii) using a combination of drugs exhibiting distinct targets and mechanisms of action; and (iii) increasing host antiviral responses. In contrast to the first DAAs, the emergence of viral resistance with recently approved DAAs, such as sofosbuvir, is less frequent but has nevertheless been described [2,243,244,245]. Given the generally lower barrier to resistance of DAAs as compared to HTAs, the emergence of treatment-resistant viral variants during DAA therapy remains a challenge. By acting through a complementary mechanism of action and by exhibiting a generally higher barrier to resistance, HTAs can be associated with DAAs to prevent viral resistance. Indeed, given their complementary mechanism of action, HTAs and DAAs can act in a synergistic manner to reduce viral loads [13,21,103] (Figure 4). Interestingly, various HTAs may also be combined to synergistically inhibit HCV infection, as demonstrated for combinations of a HTEI and host-targeting replication inhibitor, i.e., a Cyp inhibitor [21]. Furthermore, HTEIs have been demonstrated to prolong viral suppression by DAAs and to prevent viral dissemination of DAA-resistant strains in vitro [21,246,247]. Indeed, although treatment of HCV-infected cells with DAAs rapidly results in a dramatic reduction of viral load in vitro, viral rebound is usually observed following withdrawal of the drug. However, the addition of an HTEI to the cell culture at the time of DAA withdrawal allows the further decrease of the viral load, indicating that HTEIs limit viral rebound from DAA therapy [21,246]. Furthermore, as many HTEIs inhibit cell-to-cell transmission that has been shown to represent the major route of transmission of wild type and DAA-resistant viruses, HTEIs have been demonstrated to limit dissemination of DAA-resistant strains and consequently prevent antiviral resistance [247]. In line with these in vitro data, the Cyp inhibitor alisporivir, currently in phase 2/3 clinical trials, has been shown to efficiently reduce viral loads in chronic hepatitis C patients in combination with ribavirin [32] and future clinical trials evaluating its antiviral effect in combination with DAAs will provide further insights into the potential of this HTA.

Bottom Line: In contrast to DAAs that target viral proteins, host-targeting agents (HTAs) interfere with cellular factors involved in the viral life cycle.By acting through a complementary mechanism of action and by exhibiting a generally higher barrier to resistance, HTAs offer a prospective option to prevent and treat viral resistance.Indeed, given their complementary mechanism of action, HTAs and DAAs can act in a synergistic manner to reduce viral loads.

View Article: PubMed Central - PubMed

Affiliation: Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France. mirjam.zeisel@unistra.fr.

ABSTRACT
Chronic hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma (HCC) which are leading indications of liver transplantation (LT). To date, there is no vaccine to prevent HCV infection and LT is invariably followed by infection of the liver graft. Within the past years, direct-acting antivirals (DAAs) have had a major impact on the management of chronic hepatitis C, which has become a curable disease in the majority of DAA-treated patients. In contrast to DAAs that target viral proteins, host-targeting agents (HTAs) interfere with cellular factors involved in the viral life cycle. By acting through a complementary mechanism of action and by exhibiting a generally higher barrier to resistance, HTAs offer a prospective option to prevent and treat viral resistance. Indeed, given their complementary mechanism of action, HTAs and DAAs can act in a synergistic manner to reduce viral loads. This review summarizes the different classes of HTAs against HCV infection that are in preclinical or clinical development and highlights their potential to prevent HCV infection, e.g., following LT, and to tailor combination treatments to cure chronic HCV infection.

Show MeSH
Related in: MedlinePlus