Synergy of entry inhibitors with direct-acting antivirals uncovers novel combinations for prevention and treatment of hepatitis C

Xiao, Fei; Fofana, Isabel; Thumann, Christine; Mailly, Laurent; Alles, Roxane; Robinet, Éric; Meyer, Nicolás; Schaeffer, Mickaël; Habersetzer, François; Doffoël, Michel; Leyssen, Pieter; Neyts, Johan; Zeisel, Mirjam B.; Baumert, Thomas F.

doi:10.1136/gutjnl-2013-306155

Cited by 88 publications

(98 citation statements)

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“…It highlights the importance of characterizing resistance profiles of HCV, assessing readiness for treatment, and monitoring adherence patterns during treatment, so that treatment can be designed and adjusted in an evidence-based manner. This framework can be adapted easily to combination therapies based on interferon, entry inhibitors [52] or other DAA candidates, or treatments of other curable diseases without a latent reservoir.…”

Section: Discussionmentioning

confidence: 99%

“…This is especially important in resource-limited settings where patients have limited access to health care and adherence is not closely monitored. The recently developed HCV entry inhibitors [52], which inhibit host factors that are required for viral entry (instead of viral factors), may offer a promising direction for HCV combination therapy, because of their high genetic barriers to resistance, and their synergistic interactions with other classes of DAAs. For situations where therapies with low genetic barriers to resistance are used, we have identified a high-risk window period during which de novo resistance is likely if doses are missed.…”

Section: Discussionmentioning

confidence: 99%

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Rational design and adaptive management of combination therapies for Hepatitis C virus infection

Loverdo

Qi³

et al. 2014

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Recent discoveries of direct acting antivirals against Hepatitis C virus (HCV) have raised hopes of effective treatment via combination therapies. Yet rapid evolution and high diversity of HCV populations, combined with the reality of suboptimal treatment adherence, make drug resistance a clinical and public health concern. We develop a general model incorporating viral dynamics and pharmacokinetics/ pharmacodynamics to assess how suboptimal adherence affects resistance development and clinical outcomes. We derive design principles and adaptive treatment strategies, identifying a high-risk period when missing doses is particularly risky for de novo resistance, and quantifying the number of additional doses needed to compensate when doses are missed. Using data from large-scale resistance assays, we demonstrate that the risk of resistance can be reduced substantially by applying these principles to a combination therapy of daclatasvir and asunaprevir. By providing a mechanistic framework to link patient characteristics to the risk of resistance, these findings show the potential of rational treatment design. Author SummaryHepatitis C virus (HCV) affects approximately 170 million people world-wide and chronic infections can lead to cirrhosis and liver cancer. New combination therapies of direct acting antivirals have achieved remarkably high cure rates in clinical trials. However, high mutation rates and high diversity of HCV populations, combined with the reality of suboptimal treatment adherence, make drug resistance a clinical and public health concern. By constructing a mechanistic framework to assess the risk of drug resistance, we provide PLOS Computational Biology |

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Rational design and adaptive management of combination therapies for Hepatitis C virus infection

Loverdo

Qi³

et al. 2014

Preprint

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“…Il est à noter qu'il est possible d'inhiber l'infection en injectant un anticorps anti-SR-BI six heures après l'inoculation du virus [9], ce qui suggère que la fenêtre de temps pour l'administration d'un inhibiteur d'entrée, pour prévenir l'infection, n'est pas limitée à la période pré-infection. Les mécanismes de l'entrée virale jouant également un rôle dans [13,15]. ‡…”

Section: Claudine-1 : Une Cible Pour La Prévention Et Le Traitement Dunclassified

“…13 Protéine des jonctions serrées au niveau des contacts entre trois cellules. 14 Famille de virus à ARN à double brin, affectant particuliè-rement le système digestif ou le système respiratoire.…”

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“…However, because they are effective in eliminating HCV from already established infection in human liver chimeric mice and chimpanzees, HCV entry inhibitors can be candidates for an additional choice of anti-HCV treatment (8)(9)(10)(11). In particular, host-targeting agents such as BLT-1, erlotinib, and dasatinib show less opportunity for emergence of drug-resistant virus.…”

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Reply to Padmanabhan and Dixit: Hepatitis C virus entry inhibitors for optimally boosting direct-acting antiviral-based treatments

Ohashi

Koizumi

Fukano

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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We thank Padmanabhan and Dixit for their comments (1) on our paper (2). They pointed out that entry inhibitors might form potent partners for optimal drug combinations. They analyzed previously published data on 10 hepatitis C virus (HCV) entry inhibitors that are under clinical or preclinical development and found some of these HCV entry inhibitors showed high instantaneous inhibitory potentials (IIPs) (3) compared with IIPs of direct-acting antivirals (DAAs). To analyze further the utility of combining entry inhibitors with other DAAs and to extend our original results (2), we quantified the anti-HCV effect of four different classes of entry inhibitors [AR4A (anti-HCV E2 antibody) (4), BLT-1 [scavenger receptor class B type 1 (SR-BI) inhibitor] (5), erlotinib (EGF receptor inhibitor) (6), and dasatinib (EphA2 inhibitor) (6)] singly and in combination with six DAAs studied by Padmanabhan and Dixit (1) in the HCV infectious cell culture system ( Fig. 1 A and B). Single treatment of these entry inhibitors exhibited a dose-dependent reduction in HCV RNA levels. Using the median effect (1-3), we estimated IC 50 , the half-maximum inhibitory concentration, and m, the slope parameter, for each drug from its dose-response curve (Table 1), which enables us to calculate IIP = log½1 + ðD=IC 50 Þ m at D = 100 × IC 50 (i.e., IIP 100 ) (Fig. 1C). We found BLT-1 shows the highest IIP 100 among the entry inhibitors, which is equivalent in value to DAAs. In addition, applying Bliss independence (7), we quantified the upper limits of anti-HCV activity for triple-drug treatments at D = 100 × IC 50 (IIP Bcom 100 ) (Fig. 1D). These data clearly showed that HCV entry inhibitors augmented the antiviral effect of double DAA-based treatments. Interestingly, augmentation of antiviral effects by addition of entry inhibitors largely depended on the entry inhibitor used: Triple-drug treatments, including BLT-1, showed an especially high IIP Bcom 100 , which is comparable to the IIP Bcom 100 of triple DAA-based treatments, among the tested entry inhibitors.Entry inhibitors are primarily aimed at preventing viral infection. However, because they are effective in eliminating HCV from already established infection in human liver chimeric mice and chimpanzees, HCV entry inhibitors can be candidates for an additional choice of anti-HCV treatment (8-11). In particular, host-targeting agents such as BLT-1, erlotinib, and dasatinib show less opportunity for emergence of drug-resistant virus. The results of Padmanabhan and Dixit (1), which are further supported by the work reported here, show that entry inhibitors can be combined with other classes of DAAs to provide potentially potent anti-HCV treatment that may be especially effective for difficult-totreat patients.

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Synergy of entry inhibitors with direct-acting antivirals uncovers novel combinations for prevention and treatment of hepatitis C

Cited by 88 publications

References 54 publications

Rational design and adaptive management of combination therapies for Hepatitis C virus infection

Rational design and adaptive management of combination therapies for Hepatitis C virus infection

Enfermé dehors

Reply to Padmanabhan and Dixit: Hepatitis C virus entry inhibitors for optimally boosting direct-acting antiviral-based treatments

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