Case by case but most of the time I prefer my initial playthrough to be the vanilla experience. There is this intangible and impossible to describe feeling of a game going beyond just being a general improvement patch and wandering into outright being a new thing. You can never describe when someone has gone too far, but you'll know it deep down what too much means to you when you find it. Generally my ideal QoL changes are ones that stop a game from "wasting my time" though that is a nebulous concept I admit.
For example. Metroid mOTHER? Way too much change for me, it is a dope fanwork but when I want to play Metroid 1 it deviates too far from that game for me. Metroid+Saving though? Perfect! It fixes the only 2 things I really wanted from that game and that's the Famicom version's saving and the ability to save your health status so I don't need to arbitrarily grind for health everytime I reload a save. Having a map and the ability to combine wave and ice beam is also great, though I appreciate the latter change is optional since I choose to not take advantage. I've done my Metroid 1 playthrough where I made my own graph paper maps as I played and it was tons of fun, but I'm glad that I can just take advantage of +Saving's built-in map function. Basically, I feel like using passwords and having to grind for health everytime I die or take a break is just a waste that adds nothing to the atmosphere or pacing of the game, so removing those aspects doesn't feel like it cuts into the original intent of the game.
I've seen a few people say even +Saving's changes are too drastic because they are purists, and I've also seen some people refuse to play the game unless it is overhauled on the level of mOTHER. Always neat hearing people's standards for these things.
Thinking about it now, I realize most of the time I play on fan patches it usually just ends up being for 3rd and 4th generation games, typically because they add save functionality or retranslate the game to not be so cryptic or sloppy (lookin at you my beloved Breath of Fire 2).