Telaprevir (VX-950), a hepatitis C virus (HCV) NS3.4A protease inhibitor, has shown strong antiviral activity in phase 1 clinical studies. Because of high levels of HCV replication and the low fidelity of HCV polymerase, selection of resistant isolates during therapy may occur.
A highly sensitive sequencing method was developed in which approximately 80 clones/sample were analyzed to identify mutations in the NS3 protease catalytic domain in HCV genotype-1-infected patients dosed with 450 mg every 8 hours, 750 mg every 8 hours, or 1250 mg every 12 hours of telaprevir for 14 days.
Mutations that confer low-level resistance (V36A/M, T54A, R155K/T, and A156S) and high-level resistance (A156V/T, 36+155, 36+156) to telaprevir were detected and correlated with telaprevir exposure and virologic response. Changes in the frequency of mutations after the end of dosing showed an inverse relationship between in vivo viral fitness and resistance. In the absence of telaprevir selective pressure the majority of resistant variants were replaced by wild-type virus within 3-7 months.
Resistant HCV isolates are selected rapidly during therapy with the highly active protease inhibitor telaprevir. Combination therapy with pegylated interferon-alfa or other direct antiviral drugs seem mandatory to avoid developing resistance.
"The first-generation of protease inhibitors telaprevir (Vertex, Janssen, Mitsubishi) and boceprevir (Merck) were licensed for use in combination with peg-IFN and RBV in patients infected with HCV genotype 1 in 2011 (Dore et al., 2011). However, these drugs present low genetic barriers to emergence of resistant mutation (Sarrazin et al., 2007; Susser et al., 2009). A second-wave of NS3-4A protease inhibitors have reached phase II or III clinical trials, including Simeprevir (Janssen), already approved in the United States and Europe (Sheridan, 2014). "
[Show abstract][Hide abstract] ABSTRACT: Hepatitis C Virus (HCV) infects millions of people and represents an important public health problem in different regions of the world. Drug resistance is a major challenge for HCV-infection related control. Importantly, the arrival of a plethora of novel, more powerful drugs has revolutionized the field of HCV treatment. Here, we discuss the relevance of identification of HCV resistant mutants from a clinical standpoint. The advantage and limitations of molecular testing in clinical setting is presented.
American journal of infectious diseases 01/2015; 10(4):179-183. DOI:10.3844/ajidsp.2014.179.183
"Very recently, new direct antiviral agents have been approved or are under clinical trials ; these agents include NS3 protease inhibitors, NS5A inhibitors, and NS5B polymerase inhibitors   . However, the emergence of drug resistance is a serious problem associated with the use of direct antiviral agents . Host targets are alternative targets for the development of anti- HCV drugs. "
"Furthermore, data sets tracking both demographic and genetic trajectories (e.g. Sarrazin et al. 2007) are becoming increasingly available with the expansion of sequencing technologies. On the other hand, wild populations of macro-organisms present greater challenges, regarding both accurate census-taking and even identifying potential rescue situations (Gomulkiewicz and Shaw 2013). "
[Show abstract][Hide abstract] ABSTRACT: Evolutionary responses that rescue populations from extinction when drastic environmental changes occur can be friend or foe. The field of conservation biology is concerned with the survival of species in deteriorating global habitats. In medicine, in contrast, infected patients are treated with chemotherapeutic interventions, but drug resistance can compromise eradication of pathogens. These contrasting biological systems and goals have created two quite separate research communities, despite addressing the same central question of whether populations will decline to extinction or be rescued through evolution. We argue that closer integration of the two fields, especially of theoretical understanding, would yield new insights and accelerate progress on these applied problems. Here, we overview and link mathematical modelling approaches in these fields, suggest specific areas with potential for fruitful exchange, and discuss common ideas and issues for empirical testing and prediction.
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