The prevalence of the pre-existing hepatitis C viral variants and the evolution of drug resistance in patients treated with the NS3-4a serine protease inhibitor telaprevir

Journal Article · Tue Jan 01 04:00:00 EST 2008 · PLoS computational biology

OSTI ID:964948

Rong, Libin ^[1]; Ribeiro, Ruy M ^[1]; Perelson, Alan S ^[1]

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1. Los Alamos National Laboratory

Telaprevir (VX-950), a novel hepatitis C virus (HCV) NS3-4A serine protease inhibitor, has demonstrated substantial antiviral activity in patients infected with HCV genotype 1. Some patients experience viral breakthrough, which has been shown to be associated with emergence of telaprevir-resistant HCV variants during treatment. The exact mechanisms underlying the rapid selection of drug resistant viral variants during dosing are not fully understood. In this paper, we develop a two-strain model to study the pre-treatment prevalence of the mutant virus and derive an analytical solution of the mutant frequency after administration of the protease inhibitor. Our analysis suggests that the rapid increase of the mutant frequency during therapy is not due to mutant growth but rather due to the rapid and profound loss of wild-type virus, which uncovers the pre-existing mutant variants. We examine the effects of backward mutation and hepatocyte proliferation on the pre-existence of the mutant virus and the competition between wild-type and drug resistant virus during therapy. We then extend the simple model to a general model with multiple viral strains. Mutations during therapy do not play a significant role in the dynamics of various viral strains, although they are capable of generating low levels of HCV variants that would otherwise be completely suppressed because of fitness disadvantages. Hepatocyte proliferation may not affect the pretreatment frequency of mutant variants, but is able to influence the quasispecies dynamics during therapy. It is the relative fitness of each mutant strain compared with wild-type that determines which strain(s) will dominate the virus population. The study provides a theoretical framework for exploring the prevalence of pre-existing mutant variants and the evolution of drug resistance during treatment with other protease inhibitors or HCV polymerase inhibitors.

• Research Organization: Los Alamos National Laboratory (LANL)
• Sponsoring Organization: DOE
• DOE Contract Number: AC52-06NA25396
• OSTI ID: 964948
• Report Number(s): LA-UR-08-04751; LA-UR-08-4751
• Journal Information: PLoS computational biology, Journal Name: PLoS computational biology
• Country of Publication: United States
• Language: English

Related Subjects

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ANALYTICAL SOLUTION
GENOTYPE
HEPATITIS
LIVER CELLS
MUTANTS
MUTATIONS
PATIENTS
POLYMERASES
PROLIFERATION
SERINE
STRAINS
THERAPY