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Referee Comments: Referee 2

Posted by PLOS_ONE_Group on 12 May 2008 at 18:48 GMT

Referee 2's review:

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N.B. These are the comments made by the referee when reviewing an earlier version of this paper. Prior to publication, the manuscript has been revised in light of these comments and to address other editorial requirements.
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This is an interesting manuscript on the characterization of the viral genome diversity and evolution during antiviral therapy of chronic hepatitis C.

The authors have performed an extensive analysis HCV genetics in 20 patients who failed to respond to a combination of pegylated interferon and ribavirin during a clinical trial. They studied 10 patients who were non responders and 10 who were classified as relapsers. The patients were all infected with genotype 1a HCV. The authors analzyed the full length HCV genome sequence after amplification by RT-PCR in all 20 patients at treatment baseline and 6 months post-treatment. A very detailed genetic and statistical analysis was performed. They found that HCV sequences were unexpectedly stable in both responders and relapsers. Another interesting fiding, was the fact that variability in the NS2 region may have contributed to different patterns of treatment failure.
This is really an important manuscript because the authors tackled the problem of full length HCV genome analysis instead of sub-genomic region analysis as this was done by most research teams in the past. The patients' population is very homogeneous as derived from a clinical trial and included only patients with HCV genotype 1a, therefore excluding bias as found in prior studies. A very detailed statistical analysis was performed.

To improve the manuscript there are several suggestions :
1) the authors should discuss whether future work is still needed on the characterization of viral genome sequences in patients receiving interferon and ribavirin
2) the potential impact of the NS2 region variability in treatment outcome is intriguing ; could the other speculate on the potential mechanisms ?
3) the authors should also discuss whether useful information would have been generated by looking at viral genome diversity and evolution during the first weeks of therapy by comparing sustained virologic responders, non responders, and relapsers
4) the authors should also put in perspective their findings in terms of future work to be done to understand IFN - ribavirin failure, as this combination will remain the basis for the developement of new drugs which will be added to the standard of care.