The interferon sensitivity determining region: All hepatitis C virus isolates are not the same

In a follow-up report published in the New England JourSEE ARTICLES ON PAGES 740, 745, and 750 nal of Medicine, the same authors extended their results to a cohort of 84 patients treated with alpha interferon. In that study, all 30 patients with the wild-type ISDR in pretreatTo date, at least 6 genotypes and more than 40 subtypes ment serum failed to have a lasting response to alpha interof hepatitis C virus (HCV) have been described. The different feron therapy, whereas all 16 patients with the mutant type genotypes (1 through 6) are defined as having variations in (i.e., ¢4 substitutions) responded to treatment with longnucleotide sequence of 30% to 40%, subtypes (a, b, c and so term clearance of HCV RNA and improvements in serum on) by variations of 15% to 30%, and isolates (among patients) aminotransferases. of 5% to 15%. Most interestingly, however, is that HCV usuObviously, these findings needed further confirmation. In ally exists as a population of viruses with different genomic this issue of Hepatology, two groups from Japan and one from sequences even in a single patient, a phenomenon referred Europe report on their results attempting to confirm and to as ‘‘quasispecies’’ diversity. Cloning and sequencing of extend the predictive value and biological significance of seHCV RNA from the serum of a patient chronically infected quence diversity of the ISDR. Chayama et al. from Toranowith a single HCV genotype yield several quasispecies. What mon Hospital Tokyo report the results of sequencing HCV is the clinical significance of this genetic diversity of HCV RNA from 103 Japanese patients with chronic hepatitis C and how different are the different virus species and quasitreated with alpha interferon. They found a sustained respecies? sponse rate of 74% among patients with the mutant type Cross-sectional studies of patients with different genotypes ISDR sequence as compared with 12% among those with the have analyzed the potential clinical and biological signifiwild-type; patients with the intermediate type had an intercance of these variations. Initially, genotype 1b was reported mediate response rate (24%). Similarly Kurosaki and colto be associated with more severe disease and more rapid leagues from Tokyo Medical and Dental University analyzed progression to cirrhosis than other genotypes, particularly HCV RNA sequences from 22 patients with genotype 1b genotypes 2 and 3. However, this correlation was not contreated with beta interferon (a type I interferon that shares firmed in larger studies that controlled for important conreceptors with alpha interferon) and likewise found sustained founding factors that also affect severity of disease, such as responses in 67% of those with the mutant type ISDR but in duration of infection and patient age. What has held up, hownone of those with the wild-type. ever, is the correlation of genotypes with response to alpha Interestingly, the correlations between ISDR sequence and interferon therapy. In several studies from different areas of responses to alpha interferon therapy have not been conthe world, genotypes 1b and 1a have been associated with a firmed in studies outside of Japan. In this issue, Zeuzem low rate of long-term response to alpha interferon. Unforand coworkers from Frankfurt, Germany report finding little tunately, these are the most frequent genotypes in most areas correlation of response with the ISDR sequence and similar of the world. results have been reported in abstract form from other areas What accounts for the resistance of genotype 1 and particuof Europe and the United States. Why the difference? Is larly 1b infection to therapy with interferon? Interesting inthis a Japanese phenomenon? sights recently have been provided by Enomoto and colIn actuality, there are many differences in results of theraleagues from the Tokyo Medical and Dental University. They peutic trials of interferon between Japanese and US or Westnoted that HCV RNA persisted in serum during therapy in ern European studies. For instance, in most Japanese trials, patients who did not respond to alpha interferon, but that the long-term response rates have been 40% to 50%; patients the distribution of HCV quasispecies changed. To further eluwith the resistant genotype 1b having lower rates, often in cidate these changes, they sequenced the entire HCV genome the range of 25%. These rates of response are quite high from serum taken before and after therapy in three patients in comparison with US and European studies, in which the who did not respond to alpha interferon, hypothesizing that usual response rates to a 6-month course of alpha interferon therapy would lead to clearance of the interferon-sensitive has been 10% to 25%; and genotype 1b-infected patients had quasispecies leaving behind the resistant ones. Side-by-side response rates of õ10%. Can differences in the ISDR comparisons of the resulting predicted amino acid sequences account for some of the differences in these trial results? showed that the predominant virus sequence in the three To compare studies directly, we have tabulated the results patients changed and that the most consistent change ocfrom published articles and recent abstracts on the ISDR curred in the carboxy-terminal region of the NS5A gene, beusing common definitions (Table 1). The analysis is limited tween amino acids 2209 and 2248, which they named ‘‘the to patients with genotype 1b. The mutant type was defined interferon-sensitivity determining region’’ or ISDR. Isolates as originally described as four or more substitutions in the with an ISDR sequence that was the same as in the ‘‘wild type’’ genotype 1b HCV RNA were resistant to interferon, ISDR, the intermediate type as one to three substitutions, persisting in serum despite therapy. Isolates with multiple and the wild-type as complete identity with the HCV-J, the substitutions in the ISDR, referred to as the ‘‘mutant type,’’ prototype genotype 1b strain. Response to interferon was dedisappeared during interferon therapy. fined as persistent loss of HCV RNA and normal aminotransferase levels for 6 months or more after an adequate course of alpha or beta interferon. The re-analysis reveals three important points. First, the rate of response to interferon among Abbreviations: HEV, hepatitis C virus; ISDR, interferon-sensitivity determining region.