I know what you mean about going from little to big. It really drives home how much number of comments has to do with the size of the potential audience and not the quality of the fic. Rather than turning my head about the comments it made me feel better about the fewer number of comments I get on relatively smaller fandom fics because it really, honestly, is not about the writing. So writing Kirk/McCoy has actually made me more motivated to write smaller things like Ryan/Simon because I don't feel down about the smaller number of comments.

As for replying to the comments, if all they say is that they liked it, or something similarly generic, I have no problem replying to them in a fairly generic way, usually: "Thanks! I'm really glad you enjoyed it!" because that's pretty much how I feel: thank you for letting me know, that's awesome. If they say something specific I try to reply to what they said. People who read down through my replies to the comments on my fic, which are all happy and grateful because I am happy and grateful, and are annoyed that I often say the same things, honestly are putting the bar up far too high for me.