Amino Acid Substitutions in HCV Core Region Predict Poor Response to Pegylated Interferon/ribavirin in Genotype 1b Patients

By Liz Highleyman

Several factors contribute to response to interferon-based therapy for chronic hepatitis C, including HCV genotype, pre-treatment viral load, patient race/ethnicity, degree of liver fibrosis, and dose of ribavirin.

Another factor that may play a role is genetic mutations or variations in the hepatitis C virus, according to a study presented this week at the Digestive Disease Week (DDW) 2008 conference in San Diego.

As background, the study investigators noted that the HCV core protein is thought to inhibit the antiviral action of interferon by down-regulating transcription of interferon-induced antiviral genes. The core region of HCV (amino acids 30-110) is well conserved as the virus replicates, but substitutions of amino acids at positions 70 and 91 are common. Several prior studies reported a relationship between these substitutions and interferon responsiveness.

In the present analysis, the researchers evaluated whether amino acid substitutions in the core region among patients with HCV genotype 1b would affect response to pegylated interferon plus ribavirin.

The study included 145 participants. About 60% were men and the mean age was 54 years. Of the total, 61 were treatment-naive and 84 had previously been treated. All received 1.5 mcg/kg/week pegylated interferon alfa-2b (PegIntron) plus ribavirin for 48 weeks. The HCV core region was examined by direct sequencing.

Results

• 69 of the 145 patients (47.6%) achieved sustained virological response (SVR).

• 29 patients had glutamine (Gln) and 116 had arginine (Arg) at amino acid position 70.

• 46 patients had methionine (Met) and 99 had leucine (Leu) at position 91.

• 14 patients had both Gln at position 70 ("Gln70 ") and Met at position 91 ("Met91"), 2 of whom (14.3%) achieved SVR.

• Achievement of SVR occurred more frequently (50.6%) among the remaining patients without Gln at position 70 and Met at position 91 (odds ratio 6.281; P = 0.009).

• By multivariate analysis, factors associated with SVR were Gln at position 70 and Met at position 91 (odds ratio 5.40; P =0.0389).

• There were no significant differences in SVR rates with respect to patient sex, age, ALT or AST level, platelet count, previous treatment, or baseline HCV viral load.

Conclusion

Based on these findings, the investigators concluded that Gln70 and Met91 in the core region in patients with HCV genotype 1b are "significantly associated with poor response" to pegylated interferon alfa-2b and ribavirin combination therapy.

5/20/08

Reference
K Hayashi, Y Katano, T Honda, and others. Amino acid substitutions in core region of hepatitis C virus genotype 1b predict poor response to pegylated-interferon-alpha 2b and ribavirin combination therapy. Digestive Disease Week (DDW) 2008. San Diego, CA. May 17-22, 2008. Abstract S1002.