Abstract
Successful clinical drug development requires rational design of combination treatments based on preclinical data. Anti-hepatitis C virus (HCV) drugs exhibit significant diversity in antiviral effect. Dose-response assessments can be used to determine parameters profiling the diverse antiviral effect during combination treatment. In the current study, a combined experimental and mathematical approaches were used to compare and score different combinations of anti-HCV treatments. A “required concentration index” was generated and used to rank the antiviral profile of possible double- and triple-drug combinations against HCV genotype 1b and 2a. Rankings varied based on target HCV genotype. Interestingly, multidrug (double and triple) treatment not only augmented antiviral activity, but also reduced genotype-specific efficacy, suggesting another advantage of multidrug treatment. The current study provides a quantitative method for profiling drug combinations against viral genotypes, to better inform clinical drug development.
Highlights
Approved antiviral drugs rely upon dosage, treatment period, and drug combinations established during clinical trials
We have previously shown that m is unique to each anti-hepatitis C virus (HCV) drug, and that augmentation of antiviral activity with escalation of drug dose is quite diverse among the types of anti-HCV drugs [14]
In the previous study 14 anti-HCV agents were evaluated in mono and combination treatments against HCV genotype 1b [14]
Summary
Approved antiviral drugs rely upon dosage, treatment period, and drug combinations established during clinical trials. Despite the significant effort placed in clinical trials, escalation of dosage, increased treatment period, and combination. Drug concentrations which achieve 50% virus reduction (IC50), can be used to characterize drug activity. We have previously shown that m is unique to each anti-hepatitis C virus (HCV) drug, and that augmentation of antiviral activity with escalation of drug dose is quite diverse among the types of anti-HCV drugs [14]. In-depth profiling of drug antiviral effects can be useful in designing a treatment protocol with maximal antiviral efficacy.
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