Tuesday, March 6, 2012

Clinical Implications of HCV Resistance: Laying the Foundation for Optimal Treatment Today and in the Future

CCO Module
Jean-Michel Pawlotsky, MD, PhD, emphasizes the importance of optimal drug exposure and adherence levels to avoid the development of resistant hepatitis C virus variants, along with strategies to optimize adherence rates.

Learning Objectives
Upon completion of this activity, participants should be able to:
  • Evaluate the importance of optimal drug exposure for treatment success rates in HCV-infected patients receiving triple therapy
  • Explain to colleagues and patients the importance of avoiding protease inhibitor monotherapy for HCV-infected patients
  • Apply strategies to maximize adherence rates in patients receiving triple therapy for HCV infection
Importance of Pharmacokinetics and Adherence to Avoid Emergence of Resistant HCV Variants 

Source: Clinical Implications of HCV Resistance: Laying the Foundation for Optimal Treatment Today and in the Future
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.
Resistance to antiviral drugs is classically prevented by combining several drugs with potent antiviral activity and no cross-resistance. Indeed, HCV resistance to DAAs is observed significantly less frequently when one of these drugs is administered in combination with peginterferon and ribavirin.[3,4] Therefore, the triple combination of peginterferon, ribavirin, and a PI—telaprevir or boceprevir—has become the new standard-of-care therapy for both treatment-naive and treatment-experienced patients with genotype 1 HCV infection.[5-8] For the reasons defined above, it is crucial that optimal exposure to all 3 drugs in the regimen be achieved for these patients...

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