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From Clinical Care Options:

This came out today but I am not sure if it has been posted before:

Importance of Pharmokinetics and Adherance to Avoid Emergence of Resistant HCV Strains


Hepatitis C virus (HCV) resistance to a direct-acting antiviral (DAA) agent corresponds to the selection during treatment of viral variants that bear amino acid substitutions that alter the drug target; therefore, they are less susceptible to the inhibitory activity of the drug. These drug-resistant variants preexist as minor populations within the patient’s HCV quasispecies. Drug exposure profoundly inhibits replication of the dominant “wild-type” drug-sensitive viral population, and the resistant variants gradually occupy the vacant replication space. Moreover, viruses with low-level or partial resistance that can continue to replicate in the presence of drug, often favored by suboptimal drug exposure, may accumulate further mutations, leading to stepwise decreases in drug susceptibility, albeit often at a cost of reduced replicative capacity. If insufficient antiviral activity is provided because of suboptimal dosing or adherence, inadequate virologic suppression and the selection of resistance is inevitable. Therefore, to reduce the development of resistance, it is essential to achieve optimal drug concentrations through proper dosing and maximal adherence.

Factors That Influence Viral Resistance in vivo
In vivo, viral resistance is influenced by 3 major related factors: the genetic barrier to resistance, the in vivo fitness of the resistant viral population, and drug exposure.[1]

The genetic barrier to resistance is defined as the number of amino acid substitutions needed for a viral variant to acquire full resistance to the drug in question. If a single substitution is sufficient to confer high-level resistance to a specific drug, the drug is considered to have a low genetic barrier to resistance, whereas 3 or more substitutions are required to confer resistance to a drug with a high genetic barrier. There is a low likelihood that variants bearing a large number of resistance substitutions will preexist in a given patient and be fit enough to replicate at high levels when an antiviral drug is administered. Therefore, drugs with a high genetic barrier to resistance are less likely to be associated with clinically meaningful resistance.

The in vivo fitness of the viral variant is defined as its ability to survive and grow in the replicative environment. A selected resistant variant must have the capacity to propagate to fill in the replication space left vacant by the elimination of a susceptible wild-type virus during drug exposure. Thus, a highly resistant but poorly “fit” virus will be less clinically significant than a less resistant but “fitter” virus that can replicate efficiently in the presence of the drug. The acquisition of compensatory mutations may restore the fitness of a resistant variant and allow it to replicate efficiently in the presence of the drug, possibly allowing it to persist after drug withdrawal.

Finally, drug exposure affects the development of drug resistance. The degree of drug resistance of a variant can be measured in vitro as the fold increase in the 50% and 90% inhibitory concentrations (IC50 and IC90 in cell-free assays) or the 50% and 90% effective concentrations (EC50 and EC90 in cell-culture systems), that is, the drug concentrations that inhibit the tested enzyme function or viral replication by 50% and 90%, respectively. Drug exposure is defined as the drug concentration achieved in vivo relative to the IC50, IC90, EC50, or EC90 of resistant variants. This measurement is a key determinant of the development of resistance in vivo. Indeed, if drug levels achieved in vivo are far above these IC/EC values, then resistant variants will be effectively inhibited even if they are far less susceptible than the wild-type virus in vitro. Therefore, the pharmacokinetics of the antiviral drugs and adherence to therapy are key in preventing treatment failure due to viral resistance.

I have to post the next section of the article in another post  - too many characters.
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