Abstract
Mutations at positions 70 and/or 91 in the core protein of genotype-1b, hepatitis C virus (HCV) are associated with hepatocellular carcinoma (HCC) risk in Asian patients. To evaluate this in a US population, the relationship between the percentage of 70 and/or 91 mutant HCV quasispecies in baseline serum samples of chronic HCV patients from the HALT-C trial and the incidence of HCC was determined by deep sequencing. Quasispecies percentage cut-points, ≥42% of non-arginine at 70 (non-R70) or ≥98.5% of non-leucine at 91 (non-L91) had optimal sensitivity at discerning higher or lower HCC risk. In baseline samples, 88.5% of chronic HCV patients who later developed HCC and 68.8% of matched HCC-free control patients had ≥42% non-R70 quasispecies (P = 0.06). Furthermore, 30.8% of patients who developed HCC and 54.7% of matched HCC-free patients had quasispecies with ≥98.5% non-L91 (P = 0.06). By Kaplan-Meier analysis, HCC incidence was higher, but not statistically significant, among patients with quasispecies ≥42% non-R70 (P = 0.08), while HCC incidence was significantly reduced among patients with quasispecies ≥98.5% non-L91 (P = 0.01). In a Cox regression model, non-R70 ≥42% was associated with increased HCC risk. This study of US patients indicates the potential utility of HCV quasispecies analysis as a non-invasive biomarker of HCC risk.
Highlights
Are associated with hepatocellular carcinoma (HCC) risk in Asian patients
By Kaplan-Meier analysis, HCC incidence was higher, but not statistically significant, among patients with quasispecies ≥42% not coding for arginine at position 70 (non-R70) (P = 0.08), while HCC incidence was significantly reduced among patients with quasispecies ≥98.5% non-leucine at 91 (non-L91) (P = 0.01)
The presence of non-R70 amino acids before IFN treatment has been shown to be strongly associated with IFN treatment failure[28], and since our entire study group had failed IFN treatment, it is not surprising that non-R70 is highly represented in this patient group
Summary
Are associated with hepatocellular carcinoma (HCC) risk in Asian patients To evaluate this in a US population, the relationship between the percentage of 70 and/or 91 mutant HCV quasispecies in baseline serum samples of chronic HCV patients from the HALT-C trial and the incidence of HCC was determined by deep sequencing. The association of amino acid substitutions in the core protein with an increased risk of developing HCC has not previously been examined in a non-Asian population of HCV-infected patients. Akuta and colleagues recently used this type of approach to determine the impact of these positions on the risk of developing HCC after achieving an SVR17 They found that patients whose pre-treatment viral quasispecies contained ≥20% mutant sequences at position 70 had an increased incidence of HCC post-SVR. There are strong data from Japan about the importance of core protein mutations, it was not known whether they are important in a non-Asian population
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