Sustained virological response in hepatitis C virus type 1b infected patients is predicted by the number of mutations within the NS5A-ISDR: a meta-analysis focused on geographical differences

Abstract

Background and aims: There is growing evidence that the response of hepatitis C virus (HCV) genotype 1b infected patients towards interferon (IFN) therapy is influenced by the number of mutations within the carboxy terminal region of the NS5A gene, the interferon sensitivity determining region (ISDR).

Patients and methods: In order to attain better insight into this correlation, a file comprising published data on ISDR strains from 1230 HCV genotype 1b infected patients, mainly from Japan and Europe, was constructed and analysed by logistic regression. Sustained virological response (SVR) was defined as negative HCV RNA six months after treatment.

Results: The distribution of wild-, intermediate-, and mutant-type ISDR sequences differed significantly between Japanese (n = 655) (44.1%, 37.6%, and 18.3%) and European patients (n = 525) (24.8%, 63.4%, and 11.8%; p<0.001). There was a significant positive correlation between the number of ISDR mutations and SVR rate, irrespective of geographical region. The likelihood of SVR with each additional mutation within the ISDR was considerably more pronounced in Japanese compared with European patients (odds ratios 1.82 v 1.39; p<0.001). Pretreatment viraemia of <6.6 log copies/ml and ISDR mutant-type infection was associated with an SVR rate of 97.1% in Japanese patients but only 52.5% in European patients. Pretreatment viraemia was a stronger predictor of SVR than ISDR mutation number in Japanese patients whereas in European patients both parameters had similar predictive power.

Conclusion: These data support the concept that mutant-type ISDR strains may represent a subtype within genotype 1b with a more favourable response towards IFN therapy.

Figure 1

Distribution of wild-, intermediate-, and mutant-type interferon sensitivity determining region (ISDR) sequences (A) and percentage of sustained virological response (SVR) in patients infected with wild-, intermediate-, and mutant-type ISDR strains in Japan and Europe (B).

Figure 2

Frequency of mutations at each amino acid position of the interferon sensitivity determining region (ISDR) in Japanese in comparison with European patients. Differences between Japanese and European patients were tested by χ² test after Bonferroni correction by a factor 40 (equal to the number of positions tested, equal to the number of amino acids of ISDR, respectively). *ISDR positions significantly different between Japan and Europe.

Figure 3

Sustained virological response (SVR) rates according to number of mutations within the interferon sensitivity determining region (ISDR) in Japan and Europe. Significant correlation between number of ISDR mutations was noted in both Japanese and European patients. With each additional mutation, the SVR likelihood was higher in Japanese in comparison with European patients (odds ratio 1.82 v 1.39; p<0.001). Logistic regression lines are represented as broken lines and symbols.

Figure 4

Phylogenetic tree of 158 interferon sensitivity determining region (ISDR) sequences with four or more mutations recovered from 178 Japanese and European patients with a non-response or sustained virological response to treatment. The scale bars represent 10%.

Figure 5

Correlation between pretreatment viral load and number of interferon sensitivity determining region (ISDR) mutations in Japanese and European patients. Logistic regression lines are represented by continuous and broken lines, and symbols. This difference in correlations was significant (p = 0.001, interaction term between continent and ISDR mutations in a linear regression analysis for initial virus load).

Figure 6

Cumulative interferon (IFN) dosages prescribed within the first four and 24 weeks in Japanese and European patients. The circle symbol represents the mean value; bottom and top edges of the box represent 25th and 75th percentile coefficient 1; whiskers indicate range 5–95 coefficient 1.5; and asterisks (*) represent 1% and 99% percentiles (minimum and maximum).